Compounds that modulate PPAR activity and methods of preparation

ABSTRACT

This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing hyperlipidemia and hypercholesteremia in a mammal. The present invention also discloses method for making the disclosed compounds.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds and pharmaceuticalformulations that can be used to treat conditions mediated by nuclearreceptors, more specifically, to compounds and pharmaceuticalformulations that modulate PPAR activity.

BACKGROUND OF THE INVENTION

[0002] Hypercholesterolemia, hyperlipidemia, and diabetes are wellrecognized risk factors in the onset of atherosclerosis and coronaryheart disease. Hypercholesterolemia and hyperlipidemia are characterizedby excessively high levels of blood cholesterol and lipids. The bloodcholesterol pool is generally dependent on dietary uptake of cholesterolfrom the intestine and biosynthesis of cholesterol throughout the body,especially the liver. The majority of cholesterol in plasma is carriedon apolipoprotein B-containing lipoproteins, such as low-densitylipoproteins (LDL) and very-low-density lipoproteins (VLDL). The risk ofcoronary artery disease in man increases when LDL and VLDL levelsincrease. Conversely, high levels of cholesterol carried in high-densitylipoproteins (HDL) is protective against coronary artery disease (Am. J.Med., 1977; 62:707-714).

[0003] The statis represent perhaps the most important class oflipid-lowering drags. These compounds inhibit HMG-CoA reductase which isimplicated in the rate-limiting step in cellular cholesterolbiosynthesis. Representative statins include atorvastatin, lovastatin,pravastatin, and simvastatin. The effectiveness of these compoundsdepends on LDL receptor regulation. Other important antilipidemia drugsinclude fibrates such as gemfibril and clofibrate, bile acidsequestrants such as cholestyramine and colestipol, probucol, andnicotinic acid analogs.

[0004] To date, a number of oral antidiabetic agents have beendeveloped. The most commonly used hypoglygemic drugs are thesulfonylureas. Sulfonylureas are generally used to stimulate insulin.The biguanide metformin is generally used to improve insulin sensitivityand to decrease hepatic glucose output. Acarbose is used to limitpostprandial hyperglycemia. Thiazolidine 2,4 diones are used to enhanceinsulin action without increasing insulin secretion.

[0005] Peroxisome Proliferator Activation Receptors (PPAR) areimplicated in a number of biological processes and disease statesincluding hypercholesterolemia, hyperlipidemia, and diabetes. PPARs aremembers of the nuclear receptor superfamily of transcription factorsthat includes steroid, thyroid, and vitamin D receptors. They play arole in controlling expression of proteins that regulate lipidmetabolism. Furthermore, the PPARs are activated by fatty acids andfatty acid metabolites. There are three PPAR subtypes PPARα, PPARβ (alsoreferred to as PPARδ), and PPARγ. Each receptor shows a differentpattern of tissue expression, and differences in activation bystructurally diverse compounds. PPARγ, for instance, is expressed mostabundantly in adipose tissue and at lower levels in skeletal muscle,heart, liver, intestine, kidney, vascular endothelial and smooth musclecells as well as macrophages. PPAR receptors are associated withregulation of insulin sensitivity and blood glucose levels, macrophagedifferentiation, inflammatory response, and cell differentiation.Accordingly, PPARs have been associated with obesity, diabetes,carcinogenesis, hyperplasia, atherosclerosis, hyperlipidemia, andhypercholesterolemia.

[0006] In addition, PPARα agonists lower plasma triglycerides and LDLcholesterol and are therefore useful in treating hypertriglyceridemia,hyperlipidemia and obesity. PPARγ is associated with the development ofnon-insulin-dependent diabetes mellitus (NIDDM), hypertension, coronaryartery disease, hyperlipidemia and certain malignancies. Finally,activation of PPARβ has been demonstrated to increase HDL levels.(Leibowitz, WO97/28149, August 1997.) More recently, a PPARβ selectiveagonist was reported to have shown a dose-related increase in serumHDL-C and decrease in LDL-C and VLDL-TG in insulin-resistant middle agedrhesus monkeys. (W. R. Oliver et al., PNAS, v. 98, pp. 5306-5311, 2001)

[0007] Antilipidemic and antidiabetic agents are still considered tohave non-uniform effectiveness. The effectiveness of antidiabetic andantilipidemic therapies is limited, in part because of poor patientcompliance due to unacceptable side effects. These side effects includediarrhea and gastrointestinal discomfort, and in the case ofantidiabetics, edema, hypoglycemia and hepatoxicity. Furthermore, eachtype of drug does not work equally well in all patients.

[0008] For the reasons set forth above, there is a need for novelantilipidemic and antidiabetic agents that can be used alone or incombination. Furthermore, activation of PPARβ alone or in combinationwith the simultaneous activation of PPARα and/or PPARγ may be desirablein formulating a treatment for hyperlipidemia in which HDL is increasedand LDL lowered.

SUMMARY OF THE INVENTION

[0009] The present invention provides compounds capable of modulatingPPAR activity. Compounds of the present invention are described byFormula 1:

[0010] or a pharmaceutically acceptable salt thereof,

[0011] where:

[0012] V¹ is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6atoms wherein the carbon atom of position 1 is connected to the carbonatom of position 2 to form a five to eight member ring where the

[0013]  is attached to a substitutionally available position of saidring;

[0014] X⁰ and X¹ are independently O or S;

[0015] X² is absent, O, S, or NR⁴;

[0016] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0017] R¹, R², and R³are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R1 and R2 are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0018] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0019] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0020] m is 0 to 5;

[0021] n is 0 to 5; and

[0022] p is 0 to 2.

[0023] In another embodiment or the present invention, compounds ofFormula 2 are provided:

[0024] or a pharmaceutically acceptable salt thereof,

[0025] where:

[0026] V¹ is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6atoms wherein the carbon atom of position 1 is connected to the carbonatom of position 2 to form a five to eight member ring where the

[0027] is attached to a substitutionally available position of saidring;

[0028] X⁰ and X¹ are independently O or S;

[0029] X² is absent, O, S, or NR⁴;

[0030] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0031] R¹, R², and R³are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0032] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0033] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0034] m is 0 to 5;

[0035] n is 0 to 5;

[0036] p is 0 to 2; and

[0037] where T is a saturated or unsaturated, substituted orunsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain havingfrom 2 to 6 atoms wherein the carbon atom of position 3 is connected tothe carbon atom of position 4 to form a four to eight member ring.

[0038] In another embodiment of the present invention a pharmaceuticalcomposition comprising a compound of Formula 1 and one or morepharmaceutically acceptable carriers, diluents, or excipients isprovided.

[0039] In one embodiment of the present invention a method of treating,preventing or controlling hypercholesteremia in a mammal is provided.The method comprises administering to the mammal in need thereof atherapeutically effective amount of the compounds of the presentinvention.

[0040] In another embodiment of the present invention a method fortreating, preventing, or controlling obesity is provided.

[0041] In another embodiment of the present invention a method fortreating, preventing, or controlling hyperglycemia is provided.

[0042] In another embodiment of the present invention a method fortreating, preventing, or controlling hyperlipidemia is provided.

[0043] In another embodiment of the present invention a method fortreating, preventing, or controlling atherosclerosis is provided.

[0044] In another embodiment of the present invention a method fortreating, preventing, or controlling hypertriglyceridemia is provided.

[0045] In another embodiment of the present invention a method fortreating, preventing, or controlling hyperinsulinemia is provided.

[0046] In another embodiment of the present invention a method fortreating, preventing, or controlling non-insulin dependent diabetesmellitus is provided.

[0047] In another embodiment of the present invention a method fortreating a patient exhibiting glucose disorders associated withcirculating glucocorticoids, growth hormone, catecholamines, glucagon,or parathyroid hormone is provided.

[0048] For each disease state treatable, preventable, or controllable bythe method of the present invention, a therapeutically effective amountof the compounds of the present invention are administered to the mammalin need thereof.

[0049] In yet another embodiment of the present invention, a method ofpreparing the compounds of the present invention is provided.

DETAILED DESCRIPTION OF THE INVENTION

[0050] The following definitions are used, unless otherwise described:alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branchedgroups; but reference to an individual radical such as “propyl” embracesonly the straight chain radical, a branched chain isomer such as“isopropyl” being specifically referred to.

[0051] The term “alkyl” as used herein refers to a straight or branchedhydrocarbon of from 1 to 11 carbon atoms and includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also besubstituted with one or more of the substituents selected from loweralkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S,—OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆ alkyl, —CONR′R″,or —N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl,alkynyl, aryl, or joined together to form a 4 to 7 member ring. Usefulalkyl groups have from 1 to 6 carbon atoms (C₁-C₆ alkyl)

[0052] The term “lower alkyl” as used herein refers to a subset of alkylwhich means a straight or branched hydrocarbon radical having from 1 to6 carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,and the like. Optionally, lower alkyl is referred to as “C₁-C₆alkyl.”

[0053] The term “alkenyl” means a straight or branched unsaturatedhydrocarbon radical having from 2 to 12 carbon atoms and includes, forexample, ethenyl, 1-propenyl, 2propenyl, 1-butenyl, 2-butenyl,1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl,1-dodecenyl, and the like.

[0054] The term “alkynyl” means a straight or branched hydrocarbonradical having of 2 to 12 carbon atoms having at least one triple bondand includes, for example, 3-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl,3-pentynyl, 3-methyl-3-butynyl, 1-hexynyl, 3-hexynyl, 3-hexynyl,3-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl,and the like.

[0055] The term “alkylene” as used herein refers to a divalent groupderived from a straight or branched chain saturated hydrocarbon havingfrom 1 to 10 carbon atoms by the removal of two hydrogen atoms, forexample methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like. The alkylene groups of thisinvention can be optionally substituted. The alkylene group can also besubstituted with one or more of the substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro,cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ are independentlyalkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 memberring. Useful alkylene groups have from 1 to 6 carbon atoms (C₁-C₆alkylene).

[0056] The term “halogen” includes chlorine, fluorine, bromine, andiodine.

[0057] The term “heteroatom” as used herein represents oxygen, nitrogen,or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO₂)unless otherwise indicated.

[0058] The term “hydrocarbon chain” as used herein refers to a straighthydrocarbon of from 2 to 6 carbon atoms. The hydrocarbon chain isoptionally substituted with one or more substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro,cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ are independentlyalkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 memberring.

[0059] The term “hydrocarbon-heteroatom chain” as used herein refers toa hydrocarbon chain wherein one or more carbon atoms are replaced with aheteroatom. The hydrocarbon-heteroatom chain is optionally substitutedwith one or more substituents selected from lower alkyl, lower alkoxy,lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH,—SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —CONR′R″, or—N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl,alkynyl, aryl, or joined together to form a 4 to 7 member ring.

[0060] The term “heteroalkylene” as used herein, refers to an alkyleneradical as defined above that includes one or more heteroatoms such asoxygen, sulfur, or nitrogen (with valence completed by hydrogen oroxygen) in the carbon chain or terminating the carbon chain.

[0061] The terms “lower alkoxy” and “lower thioalkoxy” as used hereinrefers to O-alkyl or S-alkyl of from 1 to 6 carbon atoms as definedabove for “lower alkyl.”

[0062] The term “aryl” as used herein refers to an aromatic ring whichis unsubstituted or optionally substituted by 1 to 4 substituentsselected from lower alkyl, lower alkoxy, lower thioalkoxy,—O(CH₂)_(p)CF₃, halogen, nitro, cyano —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆alkyl, —NH₂, —NHC₁-C₆ alkyl, —SO₂alkyl, —SO₂NH₂, —CONR′R″, or—N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl, alkynylaryl, or joined together to form a 4 to 7 member ring. Examples include,but are not limited to phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl,3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl,4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl,3,4-dimethylphenyl, or the like.

[0063] The term “heteroaryl” means an aromatic ring containing one ormore heteroatoms. The heteroaryl is optionally substituted with one ormore groups enumerated for aryl. Examples of heteroaryl include, but arenot limited to thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl,imidazoyl, pyrazinyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, isoquinolinyl, and quinazolinyl, and the like.

[0064] The term “heterocycle” means a saturated or unsaturated mono- orpolycyclic (i.e. bicyclic) ring incorporating one or more (i.e. 1-4)heteroatoms selected from N, O, and S. It is understood that aheterocycle is optionally substituted with —OH, —O(alkyl), SH, S(alkyl),amine, halogen, acid, ester, amide, amidine, alkyl ketone, aldehyde,nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or C1-6 alkyl. Examplesof suitable monocyclic heterocycles include, but are not limited tosubstituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazoiyl,tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl,pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl,thietanyl, oxetaryl. Examples of monocyclic diheterocycles include, butare not limited to, 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-,or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1,3-, or 5-triazolyl, 1-, 2-, or3-tetrazolyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1- or2-piperazinyl, 2-, 3-, or 4-morpholinyl. Examples of suitable bicyclicheterocycles include, but are not limited to indolizinyl, isoindolyl,benzofuranyl, benzothienyl, or 7-indolyl, 1-, 2-, 3-, 5-, 6-, 7-, or8-indolizinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-,6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 1-, 2-, 4-,5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,and 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.

[0065] The term “heterocycloalkyl” means a nonaromatic ring with from 4to 8 members, with up to 4 heteroatoms for example, N, O, and S.Examples of heterocycloalkyl, include, but are not limited to, 2- or3-tetrahydrothieno, 2- or 3-tetrahydrofurano, 2- or 3-pyrrolidino, 2-,4-, or 5-thiazolidino, 2-, 4-, or 5-oxazolidino, 2-, 3-, or4-piperidino, N-morpholinyl or N-thiamorpholinyl or tetrahydropyrano.

[0066] The term “cycloalkyl” means a saturated hydrocarbon ring, andincludes for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, and the like. The cycloalkyl group can besubstituted with 1 to 3 substituents from the group of substituentsdescribed above for aryl. Preferrably the cycloalkyl will have from 3 to8 carbon atoms.

[0067] The term “patient” means all mammals including humans. Examplesof patients include humans, cows, dogs, cats, goats, sheep, pigs, andrabbits.

[0068] A “therapeutically effective amount” is an amount of a compoundof the present invention that when administered to a patient amelioratesa symptom of dyslipidemia, non-insulin dependent diabetes mellitus,obesity, hyperglycemia, hypercholesteremia, hyperlipidemia,atherosclerosis, hypertriglyceridemia, or hyperinsulinemia.

[0069] The term “a pharmaceutically acceptable salt” refers to therelatively non-toxic, inorganic and organic acid or base addition saltsof compounds of the present invention. These salts can be prepared insitu during the final isolation and purification of the compounds or byseparately reacting the purified compound in its free form with asuitable organic or inorganic acid or base and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, andthe like. These may include cations based on the alkali and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium,and the like, as well as non-toxic ammonium, quaternary ammonium, andamine cations including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. (See, forexample, Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977;66:1-19, which is incorporated herein by reference.) The free baseform may be regenerated by contacting the salt form with a base. Whilethe free base may differ from the salt form in terms of physicalproperties, such as solubility, the salts are equivalent to theirrespective free bases for the purposes of the present invention.

[0070] The present invention provides compounds capable of modulatingPPAR activity having Formula 1:

[0071] or a pharmaceutically acceptable salt thereof,

[0072] where:

[0073] V¹ is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6atoms wherein the carbon atom of position 1 is connected to the carbonatom of position 2 to form a five to eight member ring where the

[0074] is attached to a substitutionally available position of saidring;

[0075] X⁰ and X¹ are independently O or S;

[0076] X² is absent, O, S, or NR⁴;

[0077] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0078] R¹, R², and R³ are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0079] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0080] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0081] m is 0 to 5;

[0082] n is 0 to 5; and

[0083] p is 0 to 2.

[0084] Additional Examples of compounds of Formula 1 include those whereR¹, R², and R³ are independently hydrogen, alkyl, or alkoxy. Examples ofcompounds of Formula 1 where R¹, R², and R³ are independently alkylinclude, but are not limited to, those where R¹, R², and R³ areindependently methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, orisobutyl. Examples of compounds of Formula 1 where R¹, R², and R³ areindependently alkoxy include, but are not limited to, those where R¹,R², and R³ are independently methoxy, ethoxy, isopropoxy, n-propoxy,t-butoxy, n-butoxy, or isobutoxy.

[0085] Additional Examples of compounds of Formula 1 include those whereR¹ and R³ are hydrogen and R² is alkyl, or alkoxy. Examples of compoundsof Formula 1 where R¹ and R³ are hydrogen and R² is alkyl or alkoxyinclude, but are not limited to, those where R² is methoxy, ethoxy,isopropoxy, n-propoxy, t-butoxy, n-butoxy, isobutoxy, methyl, ethyl,isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl.

[0086] Examples of compounds of Formula 1 include those where V¹ is—CH₂CH₂CO—O—, —CH₂—CH₂—O—CO—, —CH₂—CH₂—CH₂—CH₂—, —HC═CH—HC═CH—,—N═CH—HC═CH—, —HC═N—HC═CH—, —HC═CH—N═CH—, —HC═CH—HC═N—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—, —CH₂—HC═CH—, —CH₂CH₂—NH—CH₂—, —COCH═CH—O—,—O—CH═CH—CO—, —O—CH═CH—, —CH═CH—O—, —O—CH₂—CH═CH—, —CH═CH—CH₂—O—,—CH₂—CH₂—CO—NR⁴, —CH₂—CH₂—CO—CH₂—, —CH₂—CH₂—NR⁴—CH₂—, —CH₂—NR⁴—CH₂—CH₂—,—CH═CH—NR⁴—, CH═CH—, —CH═CH—CH₂—, —CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—,—O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—,—O—CH(CH₃)—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—O—, —CH₂—CH₂—CH₂—NR⁴—,—NR⁴—CH₂—CH₂—CH₂—, —CH₂—CH₂—CO—NR⁴—, —N⁴—CO—CH₂—CH₂—, —O—NR⁴—CO—,—CO—NR⁴—O—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—, —CH₂—CH₂—NR⁴—CO—,—CH₂—CH₂—CH₂—CO—, —CO—CH₂—CH₂—CH₂—, —NR⁴—CO—CH₂—CH₂—, —CO—NR⁴—CH₂—CH₂—,—CH₂—CH₂—CO—, —CH₂—CO—CH₂—, —CH₂═CH₂—S—, —S—CH₂═CH₂—, or —CO—CH₂—CH₂—.It will be understood that the left-most atom of these groups inattached to the atom labeled “1” in Formula 1 and the right-most atom ofthese groups is attached to the atom label “1” in Formula 1.

[0087] Furthermore, examples of compounds of Formula 1 include thosewhere V¹ is optionally substituted with 1 or more substituents selectedfrom lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃,halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl,—NH₂, —NHC₁-C₆ alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ areindependently alkyl, akenyl, alkynyl, aryl, or joined together to form a4 to 7 member ring. and —N(C₁-C₆alkyl)₂.

[0088] Additional examples of compounds of Formula 1 include but are notlimited to, compounds of Formulae 1a-1h:

[0089] or a pharmaceutically acceptable salt thereof,

[0090] where:

[0091] X⁰ and X¹ are independently O or S;

[0092] X² is absent, O, S, or NR⁴;

[0093] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0094] R¹, R², and R³ are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0095] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0096] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0097] m is 0 to 5;

[0098] n is 0 to 5; and

[0099] p is 0 to 2.

[0100] Z¹, Z², Z³, and Z⁴ are independently O, S, CR⁵R⁶, NR⁴, or N; and

[0101] Z¹, Z², Z³, and Z⁴ are bonded to a sufficient number of hydrogenatoms or substituents to complete the valency of each atom with theproviso that Z¹, Z², Z³, and Z⁴ are not all heteroatoms and that notmore than two adjacent atoms in Z¹, Z², Z³, and Z⁴ are heteroatoms andthat in Formulae 1b, 1c, 1d, 1f, and 1g, Z¹, Z², Z³, and Z⁴ are not allcarbon atoms.

[0102] Additional examples of compound of Formula 1 include, but are notlimited to, those compounds of Formula 2:

[0103] or a pharmaceutically acceptable salt thereof,

[0104] wherein:

[0105] V¹ is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6atoms wherein the carbon atom of position 1 is connected to the carbonatom of position 2 to form a five to eight member ring where the

[0106] is attached to a substitutionally available position of saidring;

[0107] X⁰ and X¹ are independently O or S;

[0108] X² is absent, O, S, or NR⁴;

[0109] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0110] R¹, R², and R³are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0111] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0112] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0113] m is 0 to 5;

[0114] n is 0 to 5;

[0115] p is 0 to 2; and

[0116] where T is a saturated or unsaturated, substituted orunsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain havingfrom 2 to 6 atoms wherein the carbon atom of position 3 is connected tothe carbon atom of position 4 to form a four to eight member ring.

[0117] Examples of compounds of Formula 1 include those where T is—CH₂CH₂CO—O—, —CH₂—CH₂—O—CO—, —CH₂—CH₂—CH₂—CH₂—, —HC═CH—HC═CH—,—N═CH—HC═CH—, —HC═N—HC═CH—, —HC═CH—N═CH—, —HC═CH—HC═N—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—, —CH₂—HC═CH—, —CH₂CH₂—NH—CH₂—, —COCH═CH—O—,—O—CH═CH—CO—, —CH═CH—NR⁴—, —NR⁴—CH═CH—, —CH═CH—CH₂—, —CH₂CH₂NR⁴—,—NR⁴—CH₂—CH₂—, —O—CH₂—CH₂—, —CH₂—CH₂—O—, —CH₂—CH₂—CO—, —CH₂—CO—CH₂—,—CO—CH₂—CH₂—, —CH₂—CH₂—CH₂—CO—, —CO—CH₂—CH₂—CH₂—, —CH₂—CO—CH₂—CH₂—,—CH₂—CH₂—CO—CH₂—, —CH₂—CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—O—, —CO—NR⁴—CH₂—CH₂—, NR⁴CO—CH₂—CH₂—, —CH₂—CH₂—NR⁴—CO—, or—CH₂—CH₂—CO—NR⁴—. It will be understood that the left-most atom of thesegroups in attached to the atom labeled “4” in Formula 2 and theright-most atom of these groups is attached to the atom label “3” inFormula 2.

[0118] Furthermore, examples of compounds of Formula 1 include thosewhere T is optionally substituted with 1 or more substituents selectedfrom lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃,halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl,—NH₂, —NHC₁-C₆ alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ areindependently alkyl, akenyl, alkynyl, aryl, or joined together to form a4 to 7 member ring.

[0119] Other examples of compounds of Formula 2 include, but are notlimited to, those where V¹ is:

[0120] where:

[0121] Z¹, Z², Z³, and Z⁴ are independently O, S, CR⁵R⁶, NR⁴, or N; and

[0122] Z¹, Z², Z³, and Z⁴ are bonded to a sufficient number of hydrogenatoms or substituents (as defined above for V¹) to complete the valencyof each atom with the proviso that Z¹, Z², Z³, and Z⁴ are not allheteroatoms and that not more than two adjacent atoms in Z¹, Z², Z³, andZ are heteroatoms and that in Formulae 2a, 2b, 2c, 2d, 2g and 2h, Z¹,Z², Z³, and Z⁴ are not all carbon atoms. Accordingly, such examplesinclude those of Formulae 2a-2h:

[0123] or a pharmaceutically acceptable salt thereof,

[0124] where:

[0125] X⁰ and X¹ are independently O or S;

[0126] X² is absent, O, S, or NR⁴;

[0127] Ar¹ is substituted or unsubstituted aryl or heteroaryl;

[0128] R¹, R², and R³are independently hydrogen, lower alkyl, loweralkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH,—SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or—(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joinedtogether to form a substituted or unsubstituted, saturated orunsaturated cyloalkyl or heterocycloalkyl ring;

[0129] R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl;

[0130] R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7member ring having 0 to 3 heteroatoms;

[0131] m is 0 to 5;

[0132] n is 0 to 5;

[0133] p is 0 to 2;

[0134] T is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6atoms wherein the carbon atom of position 3 is connected to the carbonatom of position 4 to form a four to eight member ring;

[0135] Z¹, Z², Z³, and Z⁴ are independently O, S, CR⁵R⁶, NR⁴, or N; and

[0136] Z¹, Z², Z³, and Z⁴ are bonded to a sufficient number of hydrogenatoms or substituents (as defined above for V¹) to complete the valencyof each atom with the proviso that Z¹, Z², Z³, and Z⁴ are not allheteroatoms and that not more than two adjacent atoms in Z¹, Z², Z³, andZ are heteroatoms and that in Formulae 2a, 2b, 2c, 2d, 2g and 2h, Z¹,Z², Z³, and Z⁴ are not all carbon atoms.

[0137] Further examples of compounds of Formulae 1 and 2 include, butare not limited to, those where the heteroatom of thehydrocarbon-heteroatom chain is is N, O, or S.

[0138] Furthermore, examples of compounds of Formula 2 include thosewhere T is optionally substituted with 1 or more substituents selectedfrom lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃,halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl,—NH₂, —NHC₁-C₆ alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ areindependently alkyl, akenyl, alkynyl, aryl, or joined together to form a4 to 7 member ring.

[0139] Examples of compounds of Formula 1 include

[0140]5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-carboxylicacid;

[0141]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-aceticacid;

[0142]6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylicacid;

[0143]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-aceticacid;

[0144]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid;

[0145]5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylicacid;

[0146]{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}-aceticacid;

[0147]{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid;

[0148]{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid;

[0149]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic acid;

[0150]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-aceticacid;

[0151]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-aceticacid;

[0152]7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-aceticacid;

[0153]7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid;

[0154]7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid;

[0155]6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylicacid;

[0156]6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylicacid;

[0157]6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-aceticacid;

[0158]{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-aceticacid;

[0159]6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-acetic acid;

[0160]3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionic acid;

[0161] 6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-aceticacid;

[0162]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indol-1-yl}-aceticacid; and

[0163] pharmaceutically acceptable salts thereof.

[0164] Further examples of compounds of Formula 1 include

[0165]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid, (2S);

[0166]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid, (2R);

[0167]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic acid, (2R);

[0168]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-aceticacid, (2S);

[0169]6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylicacid, (2S);

[0170]6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylicacid, (2R);

[0171]2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylicacid, (2R);

[0172]2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylicacid, (2S);

[0173]{7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-aceticacid, (2S);

[0174]{7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-aceticacid, (2R); and

[0175] pharmaceutically acceptable salts thereof.

[0176] Yet further examples of compounds of Formula 1 include

[0177]{4-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid;

[0178]{2-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid;

[0179]{3-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid;

[0180]{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid;

[0181]1-Carboxymethyl-2-methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole-3-carboxylicacid ethyl ester;

[0182]{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indol-3-yl}-aceticacid;

[0183]{1-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indol-3-yl}-aceticacid;

[0184]{5-Methoxy-1-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1H-indol-3-yl}-acetic acid;

[0185]{5-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1H-indol-3-yl}-aceticacid; and

[0186] pharmaceutically acceptable salts thereof.

[0187] Yet further examples of compounds of Formula 1 include

[0188]{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid;

[0189]{6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-aceticacid; and

[0190] pharmaceutically acceptable salts thereof.

[0191] Certain of the compounds of the present invention possess one ormore chiral centers and each center may exist in the R or Sconfiguration. The present invention includes all diastereomeric,enantiomeric, and epimeric forms as well as the appropriate mixturesthereof. Stereoisomers may be obtained, if desired, by methods known inthe art as, for example, the separation of stereoisomers by chiralchromatographic columns. Additionally, the compounds of the presentinvention may exist as geometric isomers. The present invention includesall cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers aswell as the appropriate mixtures thereof.

[0192] In some situations, compounds may exist as tautomers. Alltautomers are included within Formula I and are provided by thisinvention.

[0193] In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

[0194] The present invention includes all pharmaceutically acceptable,non-toxic esters of the compounds of Formula I. Such esters includeC₁-C₆ alkyl esters wherein the alkyl group is a straight or branchedchain. Acceptable esters also include C₅-C₇ cycloalkyl esters as well asarylalkyl esters such as, but not limited to benzyl. C₁-C₄ alkyl estersare preferred. Esters of the compounds of the present invention may beprepared according to conventional methods.

[0195] The compounds of the present invention are suitable to beadministered to a patient for the treatment, control, or prevention ofnon-insulin dependent diabetes mellitus, hypercholesteremia,hyperlipidemia, obesity, hyperglycemia, hyperlipidemia, atherosclerosis,hypertriglyceridemia, and hyperinsulinemia. Accordingly, the compoundsof the present invention can be administered to a patient alone or aspart of a composition that contains other components such as excipients,diluents, and carriers, all of which are well-known in the art. Thecompositions can be administered to humans and animals either orally,rectally, parenterally (intravenously, intramuscularly, orsubcutaneously), intracisternally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray.

[0196] Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable use of a coating suchas lecithin, by the maintenance of the required particle size in thecase of dispersions and by the use of surfactants.

[0197] These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

[0198] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

[0199] Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugar as well as high molecular weightpolyethyleneglycols, and the like.

[0200] Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

[0201] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art, such as wateror other solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

[0202] Besides such inert diluents, the composition can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0203] Suspensions, in addition to the active compounds, may containsuspending agents, as for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like.

[0204] Compositions for rectal administrations are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable non-irritating excipients or carrierssuch as cocoa butter, polycthyleneglyclol, or a suppository wax, whichare solid at ordinary temperatures but liquid at body temperature andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

[0205] Dosage forms for topical administration of a compound of thisinvention include ointments, powders, sprays, and inhalants. The activecomponent is admixed under sterile conditions with a physiologicallyacceptable carrier and any preservatives, buffers, or propellants as maybe required. Ophthalmic formulations, eye ointments, powders, andsolutions are also contemplated as being within the scope of thisinvention.

[0206] The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 2,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is preferable. The specific dosage used,however, can vary. For example, the dosage can depend on a numbers offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well-known to those skilled in the art.

PREPARATION OF COMPOUNDS OF THE INVENTION

[0207] The present invention contains compounds that can be synthesizedin a number of ways familiar to one skilled in organic synthesis. Thecompounds outlined herein can be synthesized according to the methodsdescribed below, along with methods typically utilized by a syntheticchemist, and combinations or variations of those methods which aregenerally known to one skilled in the art of synthetic chemistry. Thesynthetic route of compounds in the present invention is not limited tothe methods outlined below. It is assumed one skilled in the art will beable to use the schemes outlined below to synthesize compounds claimedin this invention. Individual compounds may require manipulation of theconditions in order to accommodate various functional groups. A varietyof protecting groups generally known to one skilled in the art may berequired. Purification, if necessary, can be accomplished on a silicagel column eluted with the appropriate organic solvent system. Also,reverse phase HPLC or recrystallization may be employed as needed.

[0208] In still another embodiment of the present invention, a method ofpreparing the compounds of the present invention is provided. The methodof the present invention comprises reaction of a compound havingFormula:

[0209] in a solvent in the presence of a base such as cesium carbonatewith:

[0210] wherein

[0211] V¹,R¹, R², R³, R⁴, R⁵, R⁶, X⁰, X¹, X², Ar¹, m, n, and p are thesame as described above;

[0212] X is a halogen; and

[0213] R¹⁰ is a lower alky.

[0214] The resulting ester is then converted to the compounds ofFormulae 1 and 2 by various methods know in the art for the conversionof esters to acids, such as via hydrolysis for example. A useful arylhalide, for example, is5-chloromethyl-4-methyl-2-(4-trifluoromethy-phenyl)-thiazole. Compounds1, 1a-e, 2, 2a-e, and 3-53 will be provided when T and V¹ are defined asgiven above.

[0215] The compounds of the present invention can be prepared using thesynthetic route outlined in Scheme 1. With reference to Scheme 1,compound A is converted to the ester B. Although any compatible methodfor esterification may be used, a useful method is to react compound Awith an alcohol, such as methanol, in the presence of an acid such ashydrochloric acid. Ester B is then reacted with cholorsulfonic acid toform compound C. Compound C is then reduced to form compound D. CompoundD is then alkylated with the halide compound E to form compound F. Auseful halide compound E is5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole, forexample. Compound F is then saponified with aqueous LiOH in the THF togive the final compound G. Ar¹, X⁰, X¹, R¹, R², R³, and R⁴ are the sameas defined above for Formulas 1-2 above; X is a halogen. Compound Gcorresponds to the compounds described by Formula 1-2 above when X⁰ isS. Specifically, compound G corresponds to Formula 2 when R¹ and R² arejoined together to form a ring.

[0216] Alternatively, the compounds of the present invention can beprepared using the synthetic route outlined in Scheme 2. With referenceto Scheme 2, compound H is reacted with a reducing agent such a Dibal toform compounds with formula I. Compound I is then reacted with dimethylmalonate to form compounds with formula J. Compounds with formula J isthen reacted with cholorsulfonic acid followed by a reduction to formcompound K. Compound K is then alkylated with the halide compound E. Theresulting compound is then reacted with acid to form compound L. Auseful halide compound E is5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole, forexample. Compound L corresponds to the compounds described by Formula1-2 above when V¹ is —CH2—CH2—CH—O—, X⁰ is S, and n is 1. Specifically,compound L corresponds to Formula 2 when R¹ and R² are joined togetherto form a ring, V¹ is —CH2—CH2—CH—O—, and n is 1.

[0217] Scheme 3 provide yet another synthetic route to the compounds ofthe present invention. Compound H is reacted with cholorsulfonic acidfollowed by reduction to form compound M. Compound M is then alkylatedwith the halide compound E to form compound N. A useful halide compoundE is 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole, forexample. Compound N is reacted with a reducing agent such as Dibal toform compounds with formula O. Compound O is reacted with Wittig reagentP to form compound Q. Compound Q is then saponified with aqueous LiOH toform compound L. W, Y, Ar¹, X⁰, X¹, R¹, R², R³, and R⁴ are the same asdefined above for Formulas 1-2 above; X is a halogen. Compound Lcorresponds to the compounds described by Formula 1-2 above when X⁰ isS. Specifically, compound L corresponds to Formula 2 when R¹ and R² arejoined together to form a ring.

[0218] Another alternative synthetic route to the compounds of thepresent invention is provided in Scheme 4. Compound R may be prepared byde-methylation of the corresponding methyl ether with boron tribromide.Compound S is prepared by thiocarbamoylation of compound R. Compound Tis then prepared by a Newman-Karnes rearrangement of compound S inrefluxing diphenyl ether. Saponification and re-esterification ofcompound S then gives compound D. Compound D is then alkylated with thehalide compound E to form compound F. A useful halide compound E is5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole, forexample. Compound F is then saponified with aqueous LiOH in the THF togive the final compound G. R¹, R², R³, and R⁴ are the same as definedabove for Formulas I-IV above; X is a halogen. Compound G corresponds tothe compounds described by Formula 1-2 above. Specifically, compound Gcorresponds to Formula 2 when R¹ and R² are joined together to form aring.

[0219] The following non-limiting descriptions also demonstrate methodsfor the synthesis of compounds of Formula I.

EXAMPLE 1 Synthesis of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-carboxylicacid (Compound 1)

[0220]

Preparation of Indan-2-carboxylic acid methyl ester (Compound 1A)

[0221]

[0222] Indan-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in MeOH(50 mL) and was then treated with H₂SO₄ (1 mL). The reaction mixture wasrefluxed overnight. MeOH was evaporated and the residue was diluted withwater and ether. Layers were separated and the aqueous layer wasextracted with ether (2×30 mL). The combined organics were dried withMgSO₄ and condensed to afford the product (2.01 g, 95%) as whitecrystals.

[0223] MS: 177 (M+1)⁺

Preparation of 5-Methyl-indan-2-carboxylic acid methyl ester (Compound1B)

[0224]

[0225] Chlorosulfonic acid (5 mL) was cooled to 0° C. Then compound 1A(1.0 g, 5.68 mmol) was added over 30 min. The mixture was stirred at RTfor 3 h and was poured into ice (100 g). The cloudy solution wasextracted with ether (2×50 mL). The extracts were dried with magnesiumsulfate and concentrated to give a brown oil which was passed through ashort pad of silica gel to afford the desired product (1.17 g, 75%) aswhite plates.

[0226] MS: 259 (M-Me)⁺

Preparation of 5-Mercapto-indan-2-carboxylic acid methyl ester (Compound1C)

[0227]

[0228] The above product (1.0 g, 3.64 mmol) was refluxed with tin powder(2.2 g, 18.5 mmol) in MeOH (10 mL) and 4M HCl/dioxane (10 mL). After 3h, the reaction mixture was poured into ice with CH₂Cl₂ (50 mL). Thephases were separated and the aqueous layer was extracted with CH₂Cl₂(2×50 mL). The combined organic layers were dried with magnesiumsulfate, filtered and evaporated to give the crude thiol compound as ayellow oil (total mass: 830 mg). It was used for the next step withoutfurther purification.

[0229] MS: 207 (M−1)⁺

Preparation of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-lmethylsulfanyl]-indan-2-carboxylicacid methyl ester (Compound 1D)

[0230]

[0231] Compound 1C (crude mixture from above, 830 mg) was dissolved inacetonitrile (80 mL) with the chloride5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.50 g,1.71 mmol) and Cs₂CO₃ (2.37 g, 7.27 mmol) The reaction mixture wasstirred at RT overnight. Ether (50 mL) and H₂O were added and stirringwas continued for another 5 min. The layers were separated and theaqueous layer was extracted with ether (2×100 mL). The combined organicswas dried over MgSO₄ and concentrated to an oil. The crude product waspurified by column chromatography eluted with EtOAc and hexanes to givethe desired product as a thick yellow oil (0.48 g, 28% for 2 steps).

[0232] MS: 464 (M+1)⁺

Preparation of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-carboxylicacid (Compound 1)

[0233] To the solution of the above methyl ester (0.46 g, 0.99 mmol) inMeOH (7mL) and THF (7 mL) was added LiOH.H₂O (83 mg, 1.98 mmol). Afterrefluxing overnight, the solution was cooled to RT and solvents wereremoved by rotavap. The residue was dissolved in water and neutralizedwith 1N HCl. The cloudy solution was extracted with EtOAc (3×50 mL) andthe extracts were dried with MgSO₄and concentrated. The crude productwas purified by chromatography to afford a yellow solid, which wasfurther washed with ether to yield the desired product as yellowishcrystals (213 mg, 48%).

[0234] MS: 450 (M+1)⁺

[0235] CHN: Calc'd: C, 58.78; H, 4.04; N, 3.12. Found: C, 58.45; H,3.96; N, 2.96.

EXAMPLE 2 Synthesis of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-aceticacid (Compound 2)

[0236]

Preparation of indan-2-yl-acetic acid methyl ester (Compound 2A)

[0237]

[0238] Compound 2A was made following the procedure in Example 1, byreplacing Indan-2-carboxylic acid with indan-2-yl-acetic acid. Compound2A was prepared in 94% yield. NMR (¹H, CDCl₃): δ7.15 (5H, m), 3.69 (3H,s), 3.13 (2H, m), 2.88 (1H, m), 2.64 (2H, m), 2.49 (2H, d,j=1.97 hz):

Preparation of (5-Chlorosulfonyl-indan-2-yl)-acetic acid methyl ester(Compound 2B)

[0239]

[0240] Compound 2B was prepared according to the method of Example 1utilizing compound 2A. Compound 2B was prepared in 63% yield. MS: 253(M−Cl)⁺.

Preparation of (5-Mercapto-indan-2-yl)-acetic acid methyl ester(Compound 2C)

[0241]

[0242] Compound 2C was prepared according to the method of Example 1utilizing compound 2B. The crude product was used immediately.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-aceticacid methyl ester (Compound 2D)

[0243]

[0244] Compound 2D was prepared according to the method of Example 1utilizing compound 2C. Compound 2D was prepared in 27% yield. MS: 478(M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-aceticacid (Compound 2)

[0245] Compound 2 was prepared according to the method of example 1utilizing compound 2D. Compound 2 was prepared in 48% yield. MS: 462(M−1)⁺

EXAMPLE 3 Synthesis of6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylicacid (Compound 3)

[0246]

Preparation of Chroman-2-carboxylic acid methyl ester (Compound 3A)

[0247]

[0248] Compound 3A was prepared by hydrogenation of the methyl4-oxo-4H-chromene-2-carboxylate catalyzed by 10% Pd/C in 93% yield. MS:MS: 193 (M+1)⁺.

Preparation of 6-Chlorosulfonyl-chroman-2-carboxylic acid methyl ester(Compound 3B)

[0249]

[0250] Compound 3B was prepared according to the method of Example 1utilizing compound 3A. The crude product was used immediately.

Preparation of 6-Mercapto-chroman-2-carboxylic acid methyl ester(Compound 3C)

[0251]

[0252] Compound 3C was prepared according to the method of Example 1utilizing compound 3B. Compound 3C was prepared in 67% yield. MS: 223(M−1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylicacid methyl ester (Compound 3D)

[0253]

[0254] Compound 3D was prepared according to the method of Example 1utilizing compound 3C. Compound 3D was prepared in 49% yield. MS: 480(M+1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylicacid (Compound 3)

[0255] Compound 3 was prepared according to the method of Example 1utilizing compound 3D. Compound 3 was prepared in 58% yield. MS: 466(M+1)⁺

EXAMPLE 4 Synthesis of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-aceticacid (Compound 4)

[0256]

Preparation of (2,3-Dihydro-benzofuran-2-yl)-acetic acid methyl ester(Compound 4B)

[0257]

[0258] Compound 4B was prepared by hydrogenation of the correspondingtetrahydrofuran derivative catalyzed by 10% Pd/C in 99% yield. MS: MS:193 (M+1)⁺.

Preparation of (5-Chlorosulfonyl-2,3-dihydro-benzofuran-2-yl)-aceticacid methyl ester(Compound 4C)

[0259]

[0260] Compound 4C was prepared according to the method of Example 1utilizing compound 4B. The crude product was used immediately.

Preparation of (5-Mercapto-2,3-dihydro-benzofuran-2-yl)-acetic acidmethyl ester (Compound 4D)

[0261]

[0262] Compound 4D was prepared according to the method of Example 1utilizing compound 4C. Compound 4D was prepared in 44% yield for 2steps. MS: 223 (M−1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-aceticacid methyl ester (Compound 4E)

[0263]

[0264] Compound 4E was prepared according to the method of Example 1utilizing compound 4D in 10% yield. MS: 480 (M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-aceticacid methyl ester (Compound 4)

[0265] Compound 4 was prepared according to the method of Example 1utilizing compound 4D in 32% yield. MS: 466 (M+1)⁺

EXAMPLE 5 Synthesis of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid (Compound 5)

[0266]

Preparation of Chroman-2-ol (Compound 5A)

[0267]

[0268] Dihydrocoumarin (5 g, 33.74 mmol) was dissolved in 50 mL oftoluene and cooled to −78° C. Dibal (1 M solution in toluene, 38 mL, 38mmol) was added to the reaction flask over a 45 minutes period. Thereaction mixture was stirred at this temperature for 2 h. Water (50 mL)was added slowly along with some toluene to ensure a smooth stirring ofthe reaction mixture. The slurry was warmed to room temperature andstirring was continued overnight. The organic layer was decanted anddried with magnesium sulfate. Solvent was removed via rotatoryevaporator to give compound 5A as a clear oil (4.5 g, 89%). MS: 149(M−1)⁺

Preparation of 2-Chroman-2-yl-malonic acid dimethyl ester (Compound 5B)

[0269]

[0270] A mixture of 5A (6.77 g, 45 mmol), methyl malonate (16.8 g, 127mmol), and piperidine (0.8 g, 9.4 mmol) was stirred at 50° C. for 3 h.The reaction was worked up by adding water (150 mL), 1 N HCl (10 mL),and ether (250 mL). Layers were separated and the ether layer was driedwith magnesium sulfate. Solvent was concentrated to give compound 5B(5.6 g, 47%) as a clear oil. MS: 265 (M+1)⁺

Preparation of 2-(6-Mercapto-chroman-2-yl)-malonic acid dimethylester(Compound 5C)

[0271]

[0272] 1). Chlorosulfonic acid (15 mL) was cooled to 0° C. Then compound5B (5.5 g, 20.8 mmol) was added over 30 min. The mixture was stirred atRT for 3 h and was poured into ice (100 g). The cloudy solution wasextracted with ether (2×100 mL). The extracts were dried with magnesiumsulfate and concentrated to give the desired product (4.0 g, 53%) as ayellow oil. The crude product was used immediately for the next stepwithout purification.

[0273] 2). The above product was refluxed with tin powder (10 g, 84mmol) in MeOH (20 mL) and 4M HCl/dioxane (20 mL). After 3 h, thereaction mixture was poured into ice with CH₂Cl₂ (200 mL). The phaseswere separated and the aqueous layer was extracted with CH₂Cl₂ (2×50mL). The combined organic layers were dried with magnesium sulfate,filtered and evaporated to give the thiol compound 5C as a yellow oil(2.3 g, 37%, 2 steps). MS: 297 (M+1)⁺

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid (Compound 5)

[0274] 1). Compound 5C (200 mg, 0.67 mmol) was dissolved in acetonitrile(10 mL) with5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (200 mg,0.68 mmol) and Cs₂CO₃ (425 mg, 1.3 mmol). The reaction mixture wasstirred at RT overnight. Ether (10 mL) was added and stirring wascontinued for another 5 min. The mixture was filtered and washed withmore ether. The filtrate was concentrated and the residue was purifiedby column chromatography eluted with ether and hexanes to give thedesired product as a thick oil (85 mg, 23%). MS: 552 (M+1)⁺

[0275] 2). The above methyl ester was heated to reflux with HBr (48%, 10mL) for 30 min. The mixture was cooled to RT and HBr was removed byrotatory evaporator. Residue was dissolved in ether (20 mL) and ethylacetate (5 mL) and treated with 10 drops of saturated NaHCO₃. Themixture was stirred at RT overnight and was then filtered through a padof silica gel. The product, compound 5 crystallized in ether/hexanes(1:1) to give 12 mg white solid. MS: 480 (M+1)⁺

Alternate Synthesis of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid (Compound 5) Preparation of 6-Mercapto-chroman-2-one (Compound 5D):

[0276]

[0277] 1. To chlorosulfonic acid (15 g, 0.13 mmol) cooled at 0° C. wasadded dihydrocoumarin (4.5 g, 30 mmol) dropwise. The ice bath wasremoved and the reaction was continued for another 2 h. The reaction wasquenched by pouring the mixture into iced water (150 mL). Layers wereseparated and the aqueous layer was extract with EtOAc (3×50 mL).Combined organics were dried with MgSO₄ and filtered. Solvent wasevaporated to afford the sulfonyl cloride derivative as an off-whitesolid (4.6 g, 61%)

[0278] 2. Product from above (3.9 g, 15.8 mmol) was refluxed in HCl indioxane (4 M) with tin powder (12 g, 101 mmol) for 2 h. The reactionmixture was poured into ice-CH₂Cl₂ bath. Layers were separated and theaqueous layer was extracted with CH₂Cl₂. After drying, solvent wasremoved to afford the thio product 5D as a white solid (1.56 g, 55%).MS: 179 (M−1)⁺

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-one(Compound5E):

[0279]

[0280] Compound 5D (1.05 g, 5.8 mmol) was dissolved in THF (80 mL) withthe 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (1.40g, 5.0 mmol) and Cs₂CO₃ (3.0 g, 9.2 mmol). The reaction mixture wasstirred at RT overnight. Ether (50 mL) and H₂O were added and stirringwas continued for another 5 min. The layers were separated and theaqueous layer was extracted with ether (2×100 mL). The combined organicswas dried over MgSO₄ and concentrated to an oil. The crude product waspurified by column chromatography eluted with EtOAc and hexanes to givethe desired product 5E as an off-white solid (1.1 g, 53%). MS: 436(M+1)⁺

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-ol(Compound 5F):

[0281]

[0282] The above compound 5E (200 mg, 0.46 mmol) was dissolved intoluene (25 mL) and was cooled to −78° C. Dibal-H (1 mL, 1 M solution intoluene) was added dropwise and the reaction mixture was stirred at thistemperature for 2 h. The reaction was quenched with slow addition ofwater (0.5 mL) and stirring was continued for another 30 min. After itwas warmed to room temperature, the mixture was passed through a shortpad of MgSO₄. Solvent was removed to afford the product 5F (125 mg, 62%)MS: 438 (M+1)⁺

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid methyl ester(Compound 5G):

[0283]

[0284] Mixture of compound 5F (130 mg, 0.3 mmol) and methyl(triphenylphosphoranylidene) acetate (110 mg, 0.33 mmol) in CDCl3 (15mL) was heated to 60° C. for 2 h. After the reaction mixture was cooledto RT, ether (100 mL) was added and the mixture was passed through ashort silica gel column eluted with ether. Solvent was removed to affordcompound 5G as an off-white solid (95 mg, 65%). MS: 494 (M+1)⁺

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl}-aceticacid (Compound 5)

[0285] The above ester 5G (1.6 g, 3.2 mmol) was dissolved in THF (5 mL),MeOH (10 mL), and water (5 mL). It was treated with LiOH.H2O (200 mg,4.9 mmol) followed by refluxing for 30 min. Solvent was removed and theresidue was diluted with EtOAc (75 mL) and ether (15 mL) followed byaddition of concentrated HCl. Stirring was continued for 30 min and thesolution was passed through a short pad of MgSO₄. Solvent was removedand the product was recrystallized with ether to afford the productcompound 5 as a white solid (1.2 g, 77%). MS: 494 (M+1)⁺. CHN: Calc'd:C, 57.6; H, 4.20; N, 2.90. Found: C, 57.6; H, 3.92; N, 2.85.

EXAMPLE 6 Synthesis of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylicacid (Compound 6)

[0286]

Preparation of 5-Hydroxy-benzofuran-2-carboxylic acid methyl ester(Compound 6A)

[0287]

[0288] A solution of 5-methoxy-benzofuran-2-carboxylic acid methyl ester(5.0 g, 24 mmol) in 50 mL DCM at 0° C. was treated portionwise withboron tribromide (4.4 mL of a 1 M solution in DCM). After 3 hours, thereaction mixture was carefully quenched with 50% NH₄OH. The organiclayer was separated and washed 1×50 mL brine, dried (Na₂SO₄), andconcentrated in vacuo to give 2 g (43%) of the title compound pureenough for subsequent use. 400 MHz ¹H NMR (DMSO-d₆) δ9.47 (s, 1H), 7.56(s, 1H), 7.45 (d, 1H, J=8.8 Hz), 7.00 (s, 1H), 6.91 (d, 1H, J=8.8 Hz),3.81 (s, 3H).

Preparation of 5-Dimethylthiocarbamoyloxy-benzofuran-2-carboxylic acidmethyl ester (Compound 6B)

[0289]

[0290] A solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester(2 g, 10 mmol) in 50 mL dry DMF was treated portionwise with NaH (252 mgof a 95% dispersion in mineral oil, 10 mmol). After 30 min,dimethylthiocarbamoyl chloride (1.9 g, 15 mmol) was added and thereaction stirred at 40° C. for 1.5 hours. The reaction mixture was thenconcentrated in vacuo, and the residue taken up in EtOAc. The organiclayer was then washed 1× water, 1× brine, dried (Na₂SO₄) and the solventremoved in vacuo to give 3.5 g of the crude title compound.Recrystallization from CHCl₃/hexanes, gave 1.3 g (45%) of the titlecompound. 400 MHz ¹H NMR (DMSO-d₆) δ7.72 (s, 1H), 7.68 (d, 1H, J=9.8Hz), 7.43 (s, 1H), 7.17 (d, 1H, J=9.8Hz), 3.85 (s, 3H), 3.32 (s, 3H),3.29 (s, 3H).

Preparation of 5-Dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic acidmethyl ester (Compound 6C)

[0291]

[0292] A solution of 5-dimethylthiocarbamoyloxy-benzofuran-2-carboxylicacid methyl ester (1.3 g, 4.7 mmol) in 25 mL diphenyl ether was heatedat reflux for 2.5 hours. The reaction mixture was then cooled and theresulting precipitate collected. Purification by flash columnchromatography (gradient elution: 100% hexanes to 45% EtOAc/hexanes),gave the title compound (0.58 g, 45%) as a brown solid. 400 MHz ¹H NMR(DMSO-d₆) δ7.86 (s, 1H), 7.74 (s, 1H), 7.72 (d, 1H, J=9.0 Hz), 7.48 (d,1H, J=9.0 Hz), 3.85 (s, 3H), 3.36 (s(br), 6H); MS m/z 280 (M+1).

Preparation of 5-Mercapto-benzofuran-2-carboxylic acid methyl ester(Compound 6D)

[0293]

[0294] A solution of 5-dimethylcarbamoylsulfanyl-benzofuran-2-carboxylicacid methyl ester (0.5 g, 1.8 mmol) and potassium hydroxide (0.5 g, 12.5mmol) in 25 ml 2:1 ethanol/water was heated at reflux for 18 hours. Thereaction was then cooled, acidified with 2 M HCl, extracted 2×25 mLEtOAc, dried (Na₂SO₄) and the solvent removed in vacuo to give 350 mg ofthe crude product. The crude mixture was then refluxed overnight in 25mL MeOH and catalytic H₂SO₄. The reaction was then cooled, concentratedin vacuo, taken up in EtOAc and washed with brine. The organic layer wasthen dried (Na₂SO₄) and concentrated in vacuo to give 330 mg (95%) ofthe title compound pure enough for subsequent use. 400 MHz ¹H NMR(DMSO-d₆) δ7.66 (s, 1H), 7.62 (s, 1H), 7.57(d, 1H, J=9.0 Hz), 7.37 (d,1H, J=9.0 Hz), 5.49 (s(br), 1H), 3.85 (s, 3H).

Preparation of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylicacid methyl ester (Compound 6E)

[0295]

[0296] A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester(300 mg, 1.4 mmol) and5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg,1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed byaddition of cesium carbonate (700 mg, 2.1 mmol). The reaction was thenstirred at 60° C. for 2 hours, filtered and concentrated in vacuo.Purification by flash column chromatography (gradient elution: 5%EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg,61%) as a pale yellow solid. M.p. 132-133° C.; IR (thin film) cm⁻¹:1731; 400 MHz ¹H NMR (DMSO-d₆) δ7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H),7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s,2H), 3.82 (s, 3H); MS m/z 464 (M+1); Anal. Calc'd for C₂₂H₁₆F₃N₁O₃S₂ C,57.01; H, 3.48; N, 3.02, found: C, 56.94; H, 3.44; N, 2.84.

Preparation of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylicacid (Compound 6)

[0297] The product from example 6E (350 mg, 0.75 mmol), dissolved in 5ml THF and 1 ml water, was treated with lithium hydroxide monohydrate(159 mg, 3.75 mmol); stirring at room temperature for 1 hour. Thereaction mixture was then acidified to about pH 3 with 2 N HCl. Thereaction was then extracted into ethyl acetate (2×20 ml). The organicextracts were washed with brine, dried over anhydrous sodium sulfate,decanted, and concentrated. Recrystallization from CHCl₃/hexanes, gave232 mg (68%) of the title compound. M.p. 207-209° C.; IR (thin film)cm⁻¹: 1684; 400 MHz ¹H NMR (DMSO-d₆) δ7.95 (d, 2H, J=8.1 Hz), 7.77 (s,1H), 7.74 (d, 2H, J=8.1 Hz), 7.62 (d, 1H, J=8,8 Hz), 7.55 (s, H), 7.48(d, 1H, J=8.8 Hz), 4.43 (s, 2H); MS m/z 448 (M−1); Anal. Calc'd forC₂₁H₁₄F₃N₁O₃S₂ C, 56.12; H, 3.14; N, 3.12, found: C, 55.68; H, 3.16; N,2.98.

EXAMPLE 7 Synthesis of{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}aceticacid (Compound 7)

[0298]

Preparation of Dimethylthiocarbamic acidO-(5-oxo-5,6,7,8,-tetrahydronaphthalen-2-yl) ester (Compound 7A)

[0299]

[0300] To a solution of 4-hydroxy-1-tetralone (6.5 g, 40 mmol) inDioxane (75 mL), under nitrogen atmosphere, was addeddimethylthiocarbonyl chloride (4.9 g, 40 mmol), triethylamine (5.6 mL,40 mmol), and DMAP (0.48 g, 3.9 mmol) successively. The resultingmixture was warmed to reflux and refluxed 16 h, then diluted with waterbrine, and the organic phase dried over sodium sulfate then concentratedby roto-vap. The residue was purified by recrystallization inEtOAc/Hexane to give 5.08 g (51%) of brown solid. (mp 126-127° C.)Analyzed for C₁₃H₁₅NO₂: Calcd: C, 62.62%; H, 6.06%; N, 5.62%. Found: C,62.38%; H, 6.02%; N, 5.65%.

[0301] To solution of{6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsufanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yldene}aceticacid (0.50 g, 1.0 mmol) in chilled glacial acetic acid (3 mL) was addedzinc powder (0.30 g, 4.5 mmol). The resulting mixture was stirred 1 h,diluted with water, and extracted with EtOAc. The combined extracts werewashed with water and brine, and the organic phase dried over magnesiumsulfate and concentrated under vacuum. The residue was purified byrecrystallization in methanol to give 0.273 g (54%) of white crystals.(158-159° C.) Analyzed for C₂₄H₂₂NO₃S₂: Calcd: 58.64%; H, 4.10%; N,2.85%. Found: C, 58.94%; H, 3.97%; N, 2.69%.

Preparation of 6-Mecapto-3,4-dihydro-2H-naphthalen-1-one (Compound 7B)

[0302]

[0303] Neat dimethylthiocarbamic acidO-(5-oxo-5,6,7,8,-tetrahydronaphthalen-2-yl) ester (5.7 g, 23 mmol) washeated to 230-240° C. under nitrogen atmosphere for 1 h, then cooled toroom temperature. The residue was dissolved in methanol (100 mL), placedunder nitrogen atmosphere, and solution of 50% aqueous sodium hydroxidein water (20 mL) added. The resulting mixture was refluxed for 16 h,cooled to room temperature, acidified with 2N HCL and extracted withEtOAc. The combined extracts were washed with saturated aqueous sodiumbicarbonate and brine. The organic phase was dried over sodium sulfateand concentrated under vacuum. The residue was purified by flashchromatography (silica gel, 10% EtOAc/Hexane) to give 3.59 g (89%) of ayellow oil. NMR (400 Mhz, CDCl₃) δ2.08-2.12 (m, 2H), 2.58-2.62 (m, 2H),2.87 (t, J=6 Hz, 2H), 7.10-7.15 (m, 2H), 7.88 (d, J=8 Hz, 1H). MS: (m+1)179.

Preparation of6-[4-Methyl-2-(4-trifluoromethylpheyl)thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-naphthalen-1-one(Compound 7C)

[0304]

[0305] To a solution of 6-mercapto-3,4-dihydro-2H-naphthalen-1-one (3.5g, 20 mmol) in acetonitrile (100 mL), under nitrogen atmosphere, wasadded %-chloromethyl-4-methyl-2-(4-trifluoromethylphenyl)thiazole (5.7g, 20 mmol) followed by cesium carbonate (6.4 g, 20 mmol). The resultingmixture was stirred 16 h, diluted with water (100 mL). The precipitatewas collected by filtration, dried, dissolved in EtOAc, and filteredthrough a plug of silica gel. The filtrate was concentrated under vacuumand the residue purified by recrystallization in iso-propanol to give5.21 g (61%) of cream colored crystals. (mp 123-124° C.) Analyzed forC₂₂H₁₈F₃NOS₂: Calcd: C, 60.95%; H, 4.19%; N, 3.23%. Found: C, 60.79%; H,4.09%; N, 3.09%.

Preparation of{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene}aceticacid (Compound 7D)

[0306]

[0307] A slurry of6[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-naphthalen-1-one(2.0 g, 4.6 mmol) in glyoxylic acid monohydrate (2.0 g, reaction mixturewas cooled to room temperature, dissolved in EtOAc (100 mL) andfiltered. The filtrate was washed with water (50 mL×3) and brine. Theorganic phase was dried over magnesium sulfate, concentrated undervacuum, and purified by recrystallization in ethanol to give 1.02 g(45%) of yellow solid. Analyzed for C₂₄H₁₈NO₃S₂: Calcd: C, 58.89%; H,3.71%; N, 2.86%. Found: C, 58.715; H, 3.56%; N, 2.77.

Preparation of{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}aceticacid (Compound 7)

[0308] To solution of{6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsufanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yldene}aceticacid (0.50 g, 1.0 mmol) in chilled glacial acetic acid (3 mL) was addedzinc powder (0.30 g, 4.5 mmol). The resulting mixture was stirred 1 h,diluted with water, and extracted with EtOAc. The combined extracts werewashed with water and brine, and the organic phase dried over magnesiumsulfate and concentrated under vacuum. The residue was purified byrecrystallization in methanol to give 0.273 g (54%) of white crystals.(158-159° C.) Analyzed for C₂₄H₂₂NO₃S₂: Calcd: 58.64%; H, 4.10%; N,2.85%. Found: C, 58.94%; H, 3.97%; N, 2.69%.

EXAMPLE 8 Synthesis of{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid (Compound 8)

[0309]

Preparation of (2-Methyl-2H-chromen-2-yl)-acetic acid ethyl ester(Compound 8A)

[0310]

[0311] A suspension of 2-hydroxy-3-methylbenzylaldehyde (5.0 g, 40.9mmol) and diethyl isopropylidenemalonate (8.2 g, 40.9 mmol) in DMF (200mL) was heated to 135° C. for over night. DMF was removed by rotovap andthe residue was treated with water and EtOAc. Layers were separated andthe aqueous layer was extracted with EtOAc (100 mL×3). The combinedorganics were dried over MgSO4 and filtered. Solvent was removed and thecrude product was purified through silica gel column to give the desiredproduct as a white solid (5.98 g, 63%). MS 233 (M+1)⁺

Preparation of (2-Methyl-chroman-2-yl)-acetic acid ethyl ester (Compound8B)

[0312]

[0313] Compound 8A was hydrogenated in MeOH using 10% Pd/C as catalyst.The mixture was then filtered and washed with EtOAc. Solvent was driedto give the product as a thick oil (3.7 g, 100%). MS 235 (M+1)⁺

Preparation of (6-Chlorosulfonyl-2-methyl-chroman-2-yl)-acetic acidethyl ester (Compound 8C)

[0314]

[0315] Compound 8B (4.94 g, 21 mmol) was dissolved in CHCl₃ (100 mL) andthe solution was cooled to 0° C. Chlorosulfonic acid (4.92 g, 42 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 30min. followed by RT for 3 h. Quench the reaction with ice. Extractivework up followed by column chromatography gave the product as ayellowish oil (300 mg, 4%). MS 331 (M−1)⁺

Preparation of (6-Mercapto-2-methyl-chroman-2-yl)-acetic acid ethylester (Compound 8D)

[0316]

[0317] Compound 8D was made the same way as 1C 92% yield as a mixture ofthe methyl (major) and ethyl esters (minor). MS 265 (M+1, Et ester)⁺, MS251 (M+1, Me ester)⁺

Preparation of{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid methyl/ethyl esters (Compound 8E)

[0318]

[0319] Compound 8E was made the same way as 1D in 41% yield. The mixturewas mainly methyl ester with trace of the ethyl ester. MS 508 (M+1, Meester)⁺, MS 5221 (M+1, Et ester)⁺

Preparation of{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid (Compound 8)

[0320] Compound 8 was made from Compound 8E the same way as 1E in 58%yield. MS 494 (M+1)⁺

EXAMPLE 9 Synthesis of{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid (Compound 9)

[0321]

Preparation of (2,8-Dimethyl-chromen-2-yl)-acetic acid ethyl ester(Compound 9A)

[0322]

[0323] Compound 9A was made similar to 1A in 73% yield. MS 247 (M+1)⁺

Preparation of (2,8-Dimethyl-chroman-2-yl)-acetic acid ethyl ester(Compound 9B)

[0324]

[0325] Compound 9B was made similar to 1B in 83% yield. MS 249 (M+1)⁺

Preparation of (6-Chlorosulfonyl-2,8-dimethyl-chroman-2-yl)-acetic acidethyl ester (Compound 9C)

[0326]

[0327] Compound 9C was made similar to 1C in 96% yield. MS 311 (M−Cl)⁺

Preparation of (6-Mercapto-2,8-dimethyl-chroman-2-yl)-acetic acid methylester (Compound 9D)

[0328]

[0329] Compound 9D was made the same way as 1C using MeOH as solvent in90% yield. The ethyl ester was completely transesterified to the methylester. MS 266, M⁺

Preparation of{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid methyl ester (Compound 9E)

[0330]

[0331] Compound 9E was made the same way as 1D in 75% yield. MS 522(M+1)⁺

Preparation of{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-aceticacid (Compound 9)

[0332] Compound 9 was made the same way as 1E in 50% yield. MS 508(M+l)⁺

EXAMPLE 10 Synthesis of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoguinolin-2-yl}-aceticacid (Compound 10)

[0333]

Preparation of (3,4-Dihydro-1H-isoquinolin-2-yl)-acetic acid methylester (Compound 10A)

[0334]

[0335] Methyl bromoacetate (6.32 g, 41.3 mmol) was slowly added to astirred solution of sodium hydride (1.65 g, 41.3 mmol) and1,2,3,4-tetrahydroisoquinoline (5.0 g, 37.5 mmol). The mixture wasstirred at RT for 3 hr. After removing the solvent, the residue wasdiluted with water and ether. Layers were separated and the aqueouslayer was extracted with ether (3×50 ml). The combined organics weredried with MgSO₄ and condensed to afford the desired product 10A (5.29g, 69%) as a yellow oil. MS: 206 (M+1)⁺.

Preparation of (6-Chlorosulfonyl-3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid methyl ester (Compound 10B)

[0336]

[0337] 10B was prepared analogously to compound 1B. 24% yield. MS: 304(M+l)⁺.

Preparation of (6-Mercapto-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acidmethyl ester (Compound 10C)

[0338]

[0339] 10C was prepared analogously to compound 1C. 74% yield. MS: 238(M+1)⁺.

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid methyl ester (Compound 10D)

[0340]

[0341] Compound 10D was prepared analogously to compound 1D. Yield was6% after flash column purification. MS: 493 (M+1)⁺.

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-aceticacid(Compound 10)

[0342] Compound 10 was prepared analogously to compound 1. Compound 10was prepared in 4% yield. MS: 479 (M+1)⁺.

EXAMPLE 11 Synthesis of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-aceticacid (Compound 11)

[0343]

Preparation of (3,4-Dihydro-2H-quinolin-1-yl)-acetic acid methyl ester(Compound 11A)

[0344]

[0345] 11A was prepared analogously to compound 1A. 99% yield. MS: 206(M+l)⁺.

Preparation of (6-Chlorosulfonyl-3, 4-dihydro-2H-quinolin-1-yl)-aceticacid methyl ester (Compound 11B)

[0346]

[0347] 11B was prepared analogously to compound 1B. 12% yield. MS: 304(M+l)⁺.

Preparation of (6-Mercapto-3,4-dihydro-2H-quinolin-1-yl)-acetic acidmethyl ester (Compound 11C)

[0348]

[0349] 11C was prepared analogously to compound 1C. Used as unpurifiedoil. MS: 238 (M+1)⁺.

Preparation of{6-[4-Methyl-2-(⁴-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-aceticacid methyl ester (Compound 11D)

[0350]

[0351] Compound 11D was prepared analogously to compound 1D. Yield was40% after flash column purification. MS: 493 (M+1)⁺.

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-isoquinolin-1-yl}-aceticacid (Compound 11)

[0352] Compound 11 was prepared analogously to compound 1. Compound 11was prepared in 4% yield. MS: 479 (M+1)⁺.

EXAMPLE 12 Synthesis of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-isoguinolin-1-yl}-aceticacid (Compound 12)

[0353]

Preparation of (2-Oxo-3,4-Dihydro-2H-quinolin-1-yl)-acetic acid methylester (Compound 12A)

[0354]

[0355] 12A was prepared analogously to compound 1A. 95% yield. MS: 220(M+1)⁺.

Preparation of (6-Chlorosulfonyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetic acid methyl ester (Compound 12B)

[0356]

[0357] 12B was prepared analogously to compound 1B. 11% yield. MS: 318(M+1)⁺.

Preparation of (6-Mercapto-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-aceticacid methyl ester (Compound 12C)

[0358]

[0359] 12C was prepared analogously to compound 1C. 92% yield. MS: 252(M+1)⁺.

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-aceticacid methyl ester (Compound 12D)

[0360]

[0361] Compound 12D was prepared analogously to compound 1D. Yield was36%. MS: 507 (M+1)⁺.

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-aceticacid (Compound 12)

[0362] Compound 12 was prepared analogously to compound 1. Compound 12was prepared in 70% yield. MS: 493 (M+1)⁺.

EXAMPLE 13 Synthesis of{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-aceticacid (Compound 13)

[0363]

Preparation of (7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-aceticacid ethyl ester (Compound 13A)

[0364]

[0365] 7-Methoxy-2-tetralone (4.5 g, 25.5 mmol) in 25 ml THF was addedto a stirred solution of 1.6 M n-butyl lithium (24 ml) and triethylphosphonoacetate (8.59 g, 38.3 mmol) in 100 ml THF. The mixture wasstirred at RT overnight. Water (100 ml) was then added and the layerswere separated. The aqueous layer was extracted with ether (2×50 ml).The combined organics was dried with MgSO₄ and evaporated to give a darkoil. It was purified by silica gel chromatography eluted with 20%EtOAc/Hexanes to afford the pure product as a yellow oil (5.5 g, 88%).

[0366] Compound 13A was then prepared by hydrogenation of theunsaturated oil catalyzed by Pd/C (20%) in 90% yield. MS: 249 (M+1)⁺.

Preparation of(6-Chlorosulfonly-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl) aceticacid ethyl ester (Compound 13B)

[0367]

[0368] 13B was prepared analogously to compound 1B. 59% yield. MS: 311(M−Cl)⁺.

Preparation of(6-Mercapto-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic acidmethyl ester (Compound 13C)

[0369]

[0370] 13C was prepared analogously to compound 1C. Yield was 34% afterflash column purification. MS: 265 (M−1)⁺.

Preparation of{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-aceticacid methyl ester (Compound 13D)

[0371]

[0372] Compound 13D was prepared analogously to compound 1D. Yield was23% after flash column purification. MS: 522 (M+1)⁺.

Preparation of{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-aceticacid (Compound 13)

[0373] Compound 13 was prepared analogously to compound 1. Compound 13was prepared in 81% yield. MS: 508 (M+1)⁺.

EXAMPLE 14 Synthesis of7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid (Compound 14)

[0374]

Preparation of 7-Methoxy-chroman-2-one (Compound 14A)

[0375]

[0376] Compound 14A was prepared by hydrogenation of7-methoxy-chromen-2-one catalyzed by 10% Pd/C in 96% yield. MS: 179(M+1)⁺.

Preparation of 3-(2-Hydroxy-4-methoxy-5-thiocyanato-phenyl)-propionicacid methyl ester (Compound 14B)

[0377]

[0378] Compound 14A (3 g), KSCN (4.9 g) were dissolved in MeOH (125 mL)at 0° C., Br₂ (3 g) was added, then stirred for 2 h. The reactionmixture was quenched with water (200 mL) and ethyl acetate (200 mL). Theethyl acetate was separated and washed with water, brine, dried (MgSO₄),concentrated, to afford compound 14B (3.5 g). mp 105-016° C.; MS: 268(M+1)⁺.

Preparation of 6-Mercapto-7-methoxy-chroman-2-ol (Compound 14C)

[0379]

[0380] Compound 14B (3.5 g) was dissolved in 500 mL of toluene andcooled to −78° C. Dibal (1M solution in toluene, 40 mL) was added to thereaction over 30 minutes period. The reaction mixture was stirred atthis temperature for 2 h. Water (10 mL) was added slowly, the slurry waswarmed to room temperature, and stirring was continued overnight. Theorganic layer was decanted and dried (MgSO₄). Solvent was removed togive compound 14C as a oil (2.2 g). MS: 211(M−1)⁺.

Preparation of 6-Mercapto-7-methoxy-chroman-2-yl-acetic acid methylester (Compound 14D)

[0381]

[0382] Mixture of compound 14C (2.2 g) andmethyl-triphenyphosphoranylidene-acetate (2.2 g) in CDCl₃ (25 mL) washeated to 60° C. for 3 h. After cooled to RT, ether was added and themixture was passed through a short silical gel column, eluted withether. Solvent was removed to afford compound 14D, as a oil (150 mg).MS: 267 (M−1)⁺.

Preparation of7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid methyl ester (Compound 14E)

[0383]

[0384] Compound 14E was prepared according to the method of example 1Dutilizing compound 14D. Compound 14E was prepared in 20% yield. MS: 524(M+1)⁺.

Preparation of7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid (Compound 14)

[0385] Compound 14 was prepared according to the method of example 1utilizing compound 14E. MS: 510 (M+1)⁺.

EXAMPLE 15 Synthesis of7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid (Compound 15)

[0386]

Preparation of 7-Methyl-chroman-2-one (Compound 15A)

[0387]

[0388] Compound 15A was prepared according to the method of example 1Autilizing compound 7-methyl-chromen-2-one. MS: 163 (M+1)⁺.

Preparation of 3-(2-Hydroxy-4-methyl-5-thiocyanato-phenyl)-propionicacid methyl ester (Compound 15B)

[0389]

[0390] Compound 15B was prepared according to the method of example 1Butilizing compound 15A. MS: 252 (M+1)⁺.

Preparation of 6-Mercapto-7-methyl-chroman-2-ol (Compound 15C)

[0391]

[0392] Compound 15C was prepared according to the method of example 1Cutilizing compound 15B. MS: 195 (M−1)⁺.

Preparation of 6-Mercapto-7-methyl-chroman-2-yl-acetic acid methyl ester(Compound 15D)

[0393]

[0394] Compound 15D was prepared according to the method of example 1Dutilizing compound 15C. MS: 251 (M−1)⁺.

Preparation of7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid methyl ester (Compound 15E)

[0395]

[0396] Compound 15E was prepared according to the method of example 1Dutilizing compound 15D. Compound 15E was prepared in 45% yield. MS: 508(M+1)⁺.

Preparation of7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-aceticacid (Compound 15A)

[0397] Compound 15 was prepared according to the method of example 1utilizing compound 15E. Compound 15 was prepared in 30% yield. MS: 494(M+1)⁺.

EXAMPLE 16 Synthesis of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylicacid (Compound 16)

[0398]

Preparation of 2H-Chromene-3-carbonitrile (Compound 16A)

[0399]

[0400] 2-Hydroxy-benzaldehyde (14 g), acrylate nitrile (30.5 g) andDABCO (5.1 g) were heated to reflux for 24 h. The reaction mixture wascooled, concentrated. The crude oil was mixed with ether (300 mL) and 2NHCl (200 mL), stirred for 30 minutes. The ether layer was washed withwater, brine, dried (MgSO₄), concentrated to afford a oil compound 16A(16.8 g). MS: 158 (M+1)⁺.

Preparation of 2H-Chromene-3-carboxylic acid (Compound 16B)

[0401]

[0402] Compound 16A (16.8 g), 10% NaOH (500 mL) were heated to refluxfor 12 h. The reaction mixture was cooled to 0° C., acidified withconcentrated HCl till pH 2. The product was precipitated, filtered,dried under vacuum, to afford compound 16B, an off-white solid (13.3 g).MS: 177 (M+1)⁺.

Preparation of 2H-Chromene-3-carboxylic acid methyl ester (Compound 16C)

[0403]

[0404] Compound 16B (5 g) and concentrated HCl (2 mL) in MeOH (200 mL)were heated to reflux for 30 h. The reaction mixture was quenched withwater (200 mL) and ether (200 mL). Separated the organic layer, washedwith water, brine, dried (MgSO₄), concentrated to give an off-whitesolid, compound 16C (4.2 g). mp 56-57° C.; MS: 191 (M+1)⁺.

Preparation of 6-Chlorosulfonyl-2H-chromene-3-carboxylic acid methylester (Compound 16D)

[0405]

[0406] Compound 16D was prepared according to the method of example 1Butilizing compound 16C. The crude product was used immediately.

Preparation of 6-Mercapto-2H-chromene-3-carboxylic acid methyl ester(Compound 16E)

[0407]

[0408] Compound 16E was prepared according to the method of example 1Cutilizing compound 16D. Compound 16E was prepared in 20% yield. MS: 221(M−1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylicacid methyl ester (Compound 16F)

[0409]

[0410] Compound 16F was prepared according to the method of example 1Dutilizing compound 16E. Compound 16F was prepared in 45% yield. MS: 478(M+1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylicacid (Compound 16)

[0411] Compound 16 was prepared according to the method of example 1utilizing compound 16F. Compound 16 was prepared in 30% yield. MS: 464(M+1)⁺.

EXAMPLE 17 Synthesis of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylicacid (Compound 17)

[0412]

Preparation of Chroman-3-carboxylic acid methyl ester (Compound 17A)

[0413]

[0414] Compound 17A was prepared according to the method of example 3Autilizing compound 16C. Compound 17A was prepared in 95% yield. MS: 193(M−1)⁺.

Preparation of 6-Chlorosulfonyl-chroman-3-carboxylic acid methyl ester(Compound 17B)

[0415]

[0416] Compound 17B was prepared according to the method of example 1Butilizing compound 17A. The crude product was used immediately.

Preparation of 6-Mercapto-chroman-3-carboxylic acid methyl ester(Compound 17C)

[0417]

[0418] Compound 17C was prepared according to the method of example 1Cutilizing compound 17B. Compound PPC was prepared in 85% yield. mp83-84° C.; MS: 223 (M−1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylicacid methyl ester (Compound 17D)

[0419]

[0420] Compound 17D was prepared according to the method of example 1Dutilizing compound 17C. Compound 17D was prepared in 45% yield. MS: 480(M+1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylicacid (Compound 17)

[0421] Compound 17 was prepared according to the method of example 1utilizing compound 17D. Compound 17was prepared in 65% yield. mp139-140° C.; MS: 466 (M+1)⁺.

EXAMPLE 18 Synthesis of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-aceticacid (Compound 18)

[0422]

Preparation of Chroman-3-yl-methanol (Compound 18A)

[0423]

[0424] Compound 17A (3 g) was dissolved in 300 mL of toluene at -78° C.DibalH (1M solution in toluene, 32 mL) was added to the reaction over 30minutes period. The reaction mixture was stirred at this temperature for2 h. 2N NaOH (5 mL) was added slowly, the slurry was warmed to roomtemperature, and stirring was continued overnight. The organic layer wasdecanted and dried (MgSO₄). Solvent was removed to afford an off-whitesolid, compound 18A (2.5 g). MS: 165 (M+1)⁺.

Preparation of Toluene-4-sulfonic acid Chroman-3-ylmethyl ester(Compound 18B)

[0425]

[0426] Compound 18A (3.6 g) was dissolved in pyridine (11 mL) at RT.Toluene sulfonyl chloride (4.5 g) was added, stirred for 6 h. Thereaction mixture was quenched with 2N HCl (500 mL), ether extraction(2×200 mL). The combined ether was washed with water, brine, dried(MgSO₄), concentrated, to afford an orange color solid, compound 18B(4.2 g). mp 83-84° C.; MS: 319 (M+1)⁺.

Preparation of Chroman-3-yl-acetonitrile (Compound 18C)

[0427]

[0428] Compound 18B (1.25 g), NaCN (0.15 g) in 25 mL of DMF, were heatedto 60° C. for 12 h. The solvent was removed, the reaction mixture wasmixed with water (125 mL) and ether (125 mL). The ether layer wasseparated, washed with water, brine, dried (MgSO₄), concentrated toafford compound 18C (0.67 g). mp 54-55.5° C.; MS: 174 (M+1)⁺.

Preparation of 3-Cyanomethyl-chroman-6-sulfonyl chloride (Compound 18D)

[0429]

[0430] Compound 18D was prepared according to the method of example 1Butilizing compound 18C. The crude product was used immediately.

Preparation of 6-Mercapto-chroman-3-yl-acetonitrile (Compound 18E)

[0431]

[0432] Compound 18E was prepared according to the method of example 1Cutilizing compound 18D. Compound 18E was prepared in 35% yield. MS: 204(M−1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-acetonitrile(Compound 18F)

[0433]

[0434] Compound 18F was prepared according to the method of example 1Dutilizing compound 18E. Compound 18F was prepared in 80% yield. MS: 461(M+1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-aceticacid (Compound 18)

[0435] Compound 18F (1.5 g), MeOH (5 mL), THF (25 mL), 50% NaOH (5 mL),water (5 mL), were heated to reflux overnight. The solvent was removed.The crude reside was mixed with water (200 mL) and ether (200 mL). Themixture was acidified with 2N HCl to pH 2. The ether layer wasseparated, washed with water, brine, dried (MgSO₄), concentrated to givea oil product. The oil material was mixed with 20 mL of MeOH, stirred atRT till a white precipitate form. The solid was filtered to affordcompound 18 (0.75 g). mp 149-149.5° C.; MS: 480 (M+1)⁺.

EXAMPLE 19 Synthesis of{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-aceticacid (Compound 19)

[0436]

Preparation of (6-Methoxy-indan-1yl)-acetic acid ethyl ester (Compound19A)

[0437]

[0438] 6-Methoxy-1-indanone (5.0 g, 30.8 mmol) and triethylphosphonoacetate (13.82 g, 61.6 mmol) in THF (15 ml) was added to astirred solution of sodium hydride (2.46 g, 61.6 mmol) and ethanol (1.06g, 23.1 mmol). The mixture was heated at 80° C. overnight. Afterremoving the solvent in vacuo, the residue was diluted with water (50ml) and layered with ether (50 ml). The layers were separated and theaqueous layer extracted with ether (2×25 ml). The combined organics weredried with MgSO₄ and condensed to give a crude dark oil. It was purifiedbysilica gel chromatography eluted with 10% EtOAc/Hexanes to afford theyellow solids in 39% yield.

[0439] Compound 19A was then prepared by hydrogenation of theunsaturated solid catalyzed by Pd/C (10%) in quantitative yield. MS: 235(M+1)⁺.

Preparation of (5-Chlorosulfonyl-6-methoxy-indan-1-yl)-acetic acid ethylester (Compound 19B)

[0440]

[0441] 19B was prepared analogously to compound 1B. 39% yield. MS: 333(M+1)⁺.

Preparation of (5-Mercapto-6-methoxy-indan-1-yl)-acetic acid ethyl ester(Compound 19C)

[0442]

[0443] 19C was prepared analogously to compound 1C. Used as unpurifiedoil. MS: 267 (M+1 )⁺.

Preparation of{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-aceticacid methyl ester (Compound 19D)

[0444]

[0445] Compound 19D was prepared analogously to compound 1D. Yield was51% after flash column purification. MS: 522 (M+1)⁺.

Preparation of{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-aceticacid (Compound 19)

[0446] Compound 19 was prepared analogously to compound 1. Compound 19was prepared in 14% yield. MS: 494 (M+1)⁺.

EXAMPLE 20 Synthesis of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-aceticacid (Compound 20)

[0447]

Preparation of 4-Oxo-chroman-3-ylidene-acetic acid (Compound 20A)

[0448]

[0449] A solution of 4-chromanone (1.2 g), glyoxylic acid monohydrate (3g), NaOH (1.6 g) in 5 mL of MeOH and 5 mL of water was heated to refluxfor 2 h. The reaction mixture was concentrated, mixed with 25 mL ofwater, acidified with HCl till pH 2. The product was precipitated,filtered, washed with water, dried under vacuum to afford an off-whitesolid compound 20A (0.38 g). mp 134-136° C.; MS: 205(M+1)⁺.

Preparation of 4-Oxo-chroman-3-yl-acetic acid methyl ester (Compound20B)

[0450]

[0451] A solution of compound 20A (0.38 g), Tin powder (0.5 g), 1 mL ofMeOH, 5 mL of 4N HCl in dioxane was heated to reflux for 2 h. Thereaction mixture was cooled to 0° C., filtered the solid. The filtratewas mixed with 50 mL of ethyl acetate and 50 ml of water. The organiclayer was separated, washed with water, brine, dried (MgSO₄).Concentrated to afford compound 20B (0.4 g). MS: 221 (M+1)⁺.

Preparation of 6-Chlorosulfonyl-4-oxo-chroman-3-yl-acetic acid methylester (Compound 20C)

[0452]

[0453] Compound 20C was prepared according to the method of example 1Butilizing compound 20B. The crude product was used immediately.

Preparation of 6-Mercapto-4-oxo-chroman-3-yl-acetic acid methyl ester(Compound 20D)

[0454]

[0455] Compound 20D was prepared according to the method of example 1Cutilizing compound 20C. Compound 20D was prepared in 75% yield. MS: 251(M−1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-aceticacid methyl ester (Compound 20E)

[0456]

[0457] Compound 20E was prepared according to the method of example 1Dutilizing compound 20D. Compound 20E was prepared in 65% yield. mp93-94° C.; MS: 508 (M+1)⁺.

Preparation of6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-aceticacid (Compound 20)

[0458] Compound 20 was prepared according to the method of example 1utilizing compound 20E. Compound 20 was prepared in 10% yield. MS: 494(M+1)⁺.

EXAMPLE 21 Synthesis of3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionicacid (Compound 21)

[0459]

Preparation of 3-(2,3-Dihydro-indol-1-yl)-propionic acid methyl ester(Compound 21A)

[0460]

[0461] A solution of indoline (6.15 g), methyl 3-bromopropionate (13 g),potassium carbonate (21 g) in 150 mL of acetonitrile was refluxed fro 16h. The reaction mixture was concentrated, mixed with 300 mL of ether.The mixed reaction solution was filtered, concentrated down to affordcompound UUA (8 g). MS: 206 (M+1)⁺.

Preparation of 3-(5-Thiocyanato-2,3-dihydro-indol-1-yl)-propionic acidmethyl ester (Compound 21B)

[0462]

[0463] Compound 21B was prepared according to the method of example 14Butilizing compound 21A. Compound 21B was prepared in 80% yield. MS: 263(M−1)⁺.

Preparation of 3-(5-Mercapto-2,3-dihydro-indol-1-yl)-propionic acidmethyl ester (Compound 21C)

[0464]

[0465] Sodium borohydride (0.6 g) was added to a solution of compound21B (0.65 g) in 20 mL of MeOH at 0° C. by portion in 15 minutes period.The mixture was stirred for another 30 minutes at RT, quenched with 50mL of water and 50 mL of ether. The organic layer was separated, washedwith water, brine, dried (MgSO₄), concentrated to afford compound 21C(0.42 g). MS: 236 (M−1)⁺.

Preparation of3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionicacid methyl ester (Compound 21D)

[0466]

[0467] Compound 21D was prepared according to the method of example 1Dutilizing compound 21C. Compound 21D was prepared in 20% yield. MS: 493(M+1)⁺.

Preparation of3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionicacid (Compound 21)

[0468] Compound 21 was prepared according to the method of example 1utilizing compound 21D. Compound 21 was prepared in 60% yield. Mp 78-80°C.; MS: 479 (M+1)⁺.

EXAMPLE 22 Synthesis of 6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzoldlisoxazo-2-yl-aceticacid (Compound 22)

[0469]

Preparation of 2, N-Dihydroxy-4-methoxy-benzamide (Compound 22A)

[0470]

[0471] The 50% (w/w) NaOH (28 mL) was added to a solution of NH₂OHhydrochloride salt (13.9 g, 0.2 mole) in water (65 mL) by portion at RT.The 2-hydroxy-4-methoxy-benzoic acid methyl ester (18.2 g, 0.1 mole) indioxane (50 mL) was added dropwise, another 6 h stirred at RT. Thereaction mixture was concentrated, mixed with 300 mL of water, acidifiedwith concentrated HCl till pH 5. The product was precipitated, filtered,washed with water and dried under vacuum, to afford an off-white solidcompound 22A (17.3 g). MS: 184 (M+1)⁺.

Preparation of 6-Methoxy-benzo[d]isoxazol-3-one (Compound 22B)

[0472]

[0473] The 1,1′-carbonyldiimidazole (30.5 g) in 200 mL of THF was addeddropwise to a refluxing solution of RRA (17.3 g) in 300 mL of THF,another 1.5 h at refluxing condition. The reaction mixture wasconcentrated, mixed with 400 mL of water, acidified with concentratedHCl till PH 2. The product was precipitated, filtered, washed withwater, dried under vacuum, to afford an off-white solid compound RRB(6.1 g). MS: 166 (M+1)⁺.

Preparation of 6-Methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic acidmethyl ester (Compound 22C)

[0474]

[0475] The KN(TMS)₂ (7.2 g) was added to a solution of compound 22B (4g) in 150 mL of THF at 0° C. by portion, another one hour at 0° C. withstirring. Methyl bromoacetate (7 g) was added, stirred at RT overnight.The reaction mixture was quenched with 150 mL of ethyl acetate and 100mL of 2N HCl. The organic layer was separated, washed with water, brine,dried (MgSO₄), concentrated to afford an off-white solid compound 22C(2.5 g). mp 185-188° C.; MS: 238 (M+{)⁺.

Preparation of5-Chlorosulfonyl-6-methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic acidmethyl ester (Compound 22D)

[0476]

[0477] Compound 22D was prepared according to the method of example 1Butilizing compound 22C. The crude product was used immediately.

Preparation of 5-Mercapto-6-methoxy-3-oxo-3H-benzo disoxazol-2-yl-aceticacid methyl ester (Compound 22E)

[0478]

[0479] Compound 22E was prepared according to the method of example 1Cutilizing compound 22D. Compound 22E was prepared in 10% yield. MS: 268(M−1)⁺.

Preparation of6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazol-2-yl-aceticacid methyl ester (Compound 22F)

[0480]

[0481] Compound 22F was prepared according to the method of example 1Dutilizing compound 22E. Compound 22F was prepared in 10% yield. MS: 525(M+1)⁺.

Preparation of 6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-aceticacid (Compound 22)

[0482] Compound 22 was prepared according to the method of example 1utilizing compound 22F. Compound 22was prepared in 50% yield. mp245-247° C.; MS: 511 (M+1)⁺.

EXAMPLE 23 Synthesis of{6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-aceticacid (Compound 23)

[0483]

Preparation of 4-(3-Methoxy-phenylsulfanyl)-3-oxo-butyric acid methylester (Compound 23A)

[0484]

[0485] A solution of methyl 2-chloroacetoacetate (15.0 g, 0.10 mol) in20 ml of acetonitrile was added dropwise to a mixture of3-methoxythiophenol (14.0 g, 0.10 mol) and cesium carbonate (65.2 g,0.20 mol) in 400 ml of acetonitrile over 30 min. The mixture was stirredat room temperature for 2 hours, then filtered through Celite®. Thefiltrate was concentrated and purified using normal phasechromatography. 400 MHz ¹H NMR (CDCl₃) δ7.21 (dt, 1H), 6.95-6.85 (m,2H), 6.78 (dd, 1H), 3.82 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.65 (s,2H), MS (ES (M−1)=253).

Preparation of (6-methoxybenzo[b]thiophen-3-yl)acetic acid methyl ester(Compound 23B)

[0486]

[0487] The product from example 23A (2.54 g, 0.01 mol) was addeddropwise to 25 ml of methanesulfonic acid at room temperature, and thesolution was stirred at the same temperature for 15 minutes, then thereaction mixture was added to 250 ml of ice-water. The aqueous mixturewas extracted with ethyl acetate. The organic phase was washed withbrine, sodium bicarbonate, dried over sodium sulfate, and concentratedto give 23B in good purity. 400 MHz ¹H NMR (CDCl₃) δ7.64 (d, 1H), 7.32(d, 1H), 7.18 (s, 1H), 7.04 (dd, 1H), 3.88 (s, 3H), 3.82 (s, 2H), 3.71(s, 3H), MS (ES (M+1)=236).

Preparation of (6-hydroxy-benzo[b]thiophen-3-yl)acetic acid methyl ester(Compound 23C)

[0488]

[0489] To a stirred solution of the product from example 23B (2.20 g,9.32 mmol) in 50 ml of dichloromethane at −78° C. was added dropwise asolution of boron tribromide (11.68 g, 46.6 mmol) in 50 ml ofdichloromethane. After the completion of the addition of borontribromide, the reaction mixture was maintained at −78° C. for 1 h, thenallowed to reach room temperature and stirred at the same temperatureovernight. The mixture was cooled to 0° C., carefully quenched with 100ml of water, extracted with ethyl acetate, washed with brine, dried oversodium sulfate, concentrated, and purified using normal phasechromatography to afford the title product. 400 MHz ¹H NMR (CDCl₃) δ7.59(d, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 6.92 (dd, 1H), 5.20 (brs, 1H), 3.82(s, 2H), 3.71 (s, 3H), MS (ES (M+1)=223).

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-aceticacid methyl ester (Compound 23D)

[0490]

[0491] The title compound was prepared from compound 23C in a manneranalogous to compound 6E. MS m/z 478 (M+1).

Preparation of{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-aceticacid (Compound 23)

[0492] The title compound was prepared from compound 23D in a manneranalogous to compound 6. MS m/z 464 (M+1).

EXAMPLE 24 Synthesis of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid (Compound 24)

[0493]

Preparation of5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole(Compound 24A)

[0494]

[0495] 5-Hydroxyindole (200 mg, 1.5 mmol) was dissolved in acetonitrile(10 mL) with the chloride5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.50 g,1.7 mmol) and Cs₂CO₃ (2.37 g, 7.27 mmol) The reaction mixture wasstirred at RT overnight. Ether (50 mL) and H₂O were added and stirringwas continued for another 5 min. The layers were separated and theaqueous layer was extracted with ether (2×100 mL). The combined organicswas dried over MgSO₄ and concentrated. The crude product was purified bycolumn chromatography eluted with EtOAc and hexanes to give the desiredproduct as a white solid (0.3 g, 51% yield).

[0496] MS m/z 389 (M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid methyl ester (Compound 24B)

[0497]

[0498] Compound 24B was made from Compound 24A in the same way as 10A in56% yield.

[0499] MS m/z 461 (M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-aceticacid (Compound 24)

[0500] Compound 24 was prepared according to the method of example 1utilizing compound 24B. Compound X was prepared in 72% yield. MS m/z 447(M−1)⁺.

EXAMPLE 25 Synthesis of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indol-1-yl}-aceticacid (Compound 25)

[0501]

Preparation of (2,3-Dihydro-indol-1-yl)-acetic acid methyl ester(Compound 25A)

[0502]

[0503] Compound 25A was prepared analogously to compound 10A in 66%yield.

[0504] MS m/z 192 (M+1)⁺.

Preparation of (5-Thiocyanato-2,3-dihydro-indol-1-yl)-acetic acid methylester (Compound 25B)

[0505]

[0506] Compound 25B was prepared analogously to compound 14B in 40%yield.

[0507] MS m/z 249 (M+1)⁺.

Preparation of (5-Mercapto-2,3-dihydro-indol-1-yl)-acetic acid methylester (Compound 25C)

[0508]

[0509] Compound 25B (1.05 g, 4.2 mmol) was refluxed in a solution ofwater (2 ml), methanol (20 ml) and mercaptoacetic acid (1.2 g, 13 mmol)for 3 h. The solvent was removed under the vacuo, and the crude productwas passed a short silica gel chromatography to give 25C in 95% yield.MS m/z 224 (M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-aceticacid methyl ester (Compound 25D)

[0510]

[0511] Compound 25D was made from compound 25C the same way as compound1D in 31% yield. MS m/z 479 (M+1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indol-1-yl}-aceticacid methyl ester (Compound 25E)

[0512]

[0513] Compound 25D (600 mg, 1.3 mmol), and tetrachloro-1,2-benzoquinone(300 mg, 1.3 mmol) were stirred in 10 ml anhydrous ether at RT for 1 h.The compound 25E was purified using normal phase chromatography in 15%yield. MS m/z 447 (M−1)⁺.

Preparation of{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indol-1-yl}-aceticacid (Compound 25)

[0514] Compound 25 was prepared according to the method of example 1utilizing compound 25E. Compound 25 was prepared in 97% yield. MS m/z463 (M−1)⁺.

BIOLOGICAL ASSAYS

[0515] The compounds of the present invention have demonstrated PPARmodulating activity in the standard assays commonly employed by thoseskilled in the art. Accordingly, such compounds and formulationscomprising such compounds are useful for treating, preventing orcontrolling dyslipidemia in a mammal.

[0516] A. Selectivity Measurements

[0517] 1. Test A. Transient transfections assay using the HepG2 hepatomacell line.

[0518] HepG2 cells were transiently transfected with an expressionplasmids encoding hPPARα, hPPARβ or mPPARγ chimeric receptors and areporter containing the yeast upstream activating sequence (UAS)upstream of the viral E1B promoter controlling a luciferase reportergene. In addition, the plasmid pRSVβ-gal was used to control fortransfection efficiency. HepG2 cells were grown in DMEM supplementedwith 10% FBS and 1 μM non-essential amino acid. On the first day, cellswere split into 100 mm dishes at 2.5×10⁶/dish and incubated overnight at37° C./5% CO₂. On the second day the cells were transiently transfectedwith plasmid DNA encoding a chimeric receptor, the luciferase reportergene; and β-gal. For each 100 mm dish, 15 μg of lucifease reporter(PG5E1b) DNA, 15 μg of Gal4-PPAR chimeric receptor DNA, and 1.5 μg ofβ-gal plasmid DNA were mixed with 1.4 ml of opti-MEM in the tube. 28 μlof LipoFectamine-2000 reagent was added to 1.4 ml of opti-MEM in thetube, and incubate for 5 min at RT. The diluted Lipofectamine-2000reagent was combined with the DNA mixture, and incubate for 20 min atRT. After fresh medium was added to each 100 mm dish of cells, 2.8 ml ofLipofectamine2000-DNA mixture was added dropwise to the 100 mm dishcontaining 14 ml of medium, and incubate 37° C. overnight. On day threecells were trypsinized off the 100 mm dishes and re-plated on 96 wellplates. Cells were plated at 2.5×10⁴ cells per well in 150 μl of mediaand 50 μl of compound diluted by media was added. The concentrations ofreference agents and test compound added were in the range from 50 μM to50 μM. After addition of compounds, the plates were incubated at 37° C.for 24 hours. Subsequently cells were washed once with 100 μl of PBS,lysed, and processed for measuring luciferase and β-gal activity usingDual-Light luciferase kit from Tropix®, according to the manufacturer'srecommendations, on an EG&G Bethold MicroLumat LB96P luminometer. EC₅₀values were obtained using the GraphPad Prism™ program. Surprisingly,the compounds of the present invention exhibit activity for both PPARαand PPARβ. Accordingly, the compounds of the present invention shouldfind considerable therapeutic applications for hypercholesterolemia andhyperlipidemia. The Hep G2-hBeta EC₅₀ (“EC₅₀β”) data as well as the HepG2-hAlpha IEC₅₀ (“EC₅α”) data of the compounds of the invention arepresented in Table 1 below. TABLE 1 Example Hep G2-hβ EC₅₀ nM HepG2-hαEC₅₀ nM 1 177.7 384 2 267.4 1957 3 762.0 917 4 1542 899 5 8.33737.75 6 2000000 2044 7 614.0 — 8 3470.0 — 9 2000000 — 10 111.1 — 11286.0 1928 12 896.1 2000000 13 24.1 1190 14 19.0 2000000 15 252.2 130116 2210.0 — 17 2130.0 2185 18 394.0 1002254.5 19 113.0 42 20 — — 21 — —22 2000000 — 23 1.7 572.0 24 — — 25 — —

FORMULATIONS

[0519] The compounds of the present invention can be administered aloneor in combination with one or more therapeutic agents. These include,for example, other agents for treating, preventing or controllingdyslipidemia, non-insulin dependent diabetes mellitus, obesity,hyperglycemia, hypercholesteremia, hyperlipidemia, antherosclerosis,hypertriglyceridemia, or hyperinsulinemia.

[0520] The compounds are thus well suited to formulation for convenientadministration to mammals for the prevention and treatment of suchdisorders.

[0521] The following examples further illustrate typical formulationsprovided by the invention. Formulation 1 Ingredient Amount compound ofFormulas 1-50 0.5 to 800 mg sodium benzoate   5 mg isotonic saline 1000mL

[0522] The above ingredients are mixed and dissolved in the saline forIV administration to a patient. Formulation 2 Ingredient Amount compoundof Formulas 1-50 0.5 to 800 mg cellulose, microcrystalline 400 mgstearic acid  5 mg silicon dioxide  10 mg sugar, confectionery  50 mg

[0523] The ingredients are blended to uniformity and pressed into atablet that is well suited for oral administration to a patient.Formulation 3 Ingredient Amount compound of Formulas 1-50 0.5 to 800 mgstarch, dried 250 mg magnesium stearate  10 mg

[0524] The ingredients are combined and milled to afford materialsuitable for filling hard gelatin capsules administered to a patient.Formulation 4 Ingredient Amount % wt./(total wt.) compound of Formulas1-50  1 to 50 Polyethylene glycol 1000 32 to 75 Polyethylene glycol 400016 to 25

[0525] The ingredients are combined via melting and then poured intomolds containing 2.5 g total weight.

[0526] While embodiments of the invention have been illustrated anddescribed, it is not intended that these embodiments illustrate anddescribe all possible forms of the invention. Rather, the words used inthe specification are words of description rather than limitation, andit is understood that various changes may be made without departing fromthe spirit and scope of the invention.

What is claimed is:
 1. A compound having formula 1:

or a pharmaceutically acceptable salt thereof, wherein: V¹ is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 1 is connected to the carbon atom of position 2 to form a five to eight member ring wherein the

is attached to a substitutionally available position of said ring; X⁰ and X¹ are independently O or S; X² is absent, O, S, or NR⁴; Ar¹ is substituted or unsubstituted aryl or heteroaryl; R¹, R², and R³ are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or —(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring; R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; and p is 0 to
 2. 2. The compound of claim 1, wherein: V¹ is —CH₂CH₂CO—O—, —CH₂—CH₂—O—CO—, —CH₂—CH₂—CH₂—CH₂—, —HC═CH—HC═CH—, —N═CH—HC═CH—, —HC═N—HC═CH—, —HC═CH—N═CH—, —HC═CH—HC═N—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—HC═CH—, —CH₂CH₂—NH—CH₂—, 13 COCH═CH—O—, —O—CH═CH—CO—, —O—CH═CH—, —CH═CH—O—, —O—CH₂—CH═CH—, —CH═CH—CH₂—O—, —CH₂—CH₂—CO—NR⁴, —CH₂—CH₂—CO—CH₂—, CH₂—CH₂—NR⁴—CH₂—, —CH₂—NR⁴—CH₂—CH₂—, —CH═CH—NR⁴—, —NR⁴—CH═CH—, —CH═CH—CH₂—, —CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—, —O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —O—CH(CH₃)—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—O—, —CH₂—CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—CH₂—, —CH₂—CH₂—CO—NR⁴—, —NR⁴—CO—CH₂—CH₂—, —O—NR⁴—CO—, —CO—NR⁴—O—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—, —CH₂—CH₂—NR⁴—CO—, —CH₂—CH₂—CH₂—CO—, —CO—CH₂—CH₂—CH₂—, —NR⁴—CO—CH₂—CH₂—, —CO—NR⁴—CH₂—CH₂—, —CH₂—CH₂—CO—, —CH₂—CO—CH₂—, —CH₂═CH₂S—, —S—CH₂═CH₂—, or —CO—CH₂—CH₂—.
 3. The compound of claim 2 wherein: V¹ is substituted with 1 or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆ alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂; and R′ and R″ are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. and —N(C₁-C₆alkyl)₂.
 4. The compound of claim 1 having Formula 1a, Formula 1b, Formula 1c, Formula 1d, Formula 1e, Formula 1f, Formula 1f, Formula 1g, or Formula 1h:

or a pharmaceutically acceptable salt thereof, wherein: X⁰ and X¹ are independently O or S; X² is absent, O, S, or NR⁴; Ar¹ is substituted or unsubstituted aryl or heteroaryl; R¹, R², and R³ are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or —(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring; R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; and p is 0 to
 2. Z¹, Z², Z³, and Z⁴ are independently O, S, CR⁵R⁶, NR⁴, or N; and Z¹, Z², Z³, and Z⁴ are bonded to a sufficient number of hydrogen atoms or substituents to complete the valency of each atom with the proviso that Z¹, Z², Z³, and Z⁴ are not all heteroatoms and that not more than two adjacent atoms in Z¹, Z², Z³, and Z⁴ are heteroatoms and that in Formulae 1b, 1c, 1d, 1f, and 1g, Z¹, Z², Z³, and Z⁴ are not all carbon atoms.
 5. The compound of claim 1, wherein: R¹, R², and R³ are independently hydrogen, alkyl, or alkoxy.
 6. The compound of claim 1, wherein: R¹ and R³ are hydrogen; and R² is alkyl or alkoxy.
 7. The compound of claim 1, wherein: R¹ and R³ are hydrogen; and R² is alkoxy.
 8. The compound of claim 1, wherein: R¹ and R³ are independently hydrogen, methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl; and R² is methyoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, or isobutoxy.
 9. The compound having Formula 2:

or a pharmaceutically acceptable salt thereof, wherein: V¹ is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 1 is connected to the carbon atom of position 2 to form a five to eight member ring wherein the

is attached to a substitutionally available position of said ring; X⁰ and X¹ are independently O or S; X² is absent, O, S, or NR⁴; Ar¹ is substituted or unsubstituted aryl or heteroaryl; R¹, R², and R³ are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or —(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring; R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; p is 0 to 2; and wherein T is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6 atoms wherein the carbon atom of position 3 is connected to the carbon atom of position 4 to form a four to eight member ring.
 10. The compound of claim 9 having Formula 2a, Formula 2b, Formula 2c, Formula 2d, Formula 2e, Formula 2f, Formula 2g, or Formula 2h:

or a pharmaceutically acceptable salt thereof, wherein: X⁰ and X¹ are independently O or S; X² X is absent, O, S, or NR⁴; Ar¹ is substituted or unsubstituted aryl or heteroaryl; R¹, R², and R³ are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or —(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, or —NR⁵R⁶ or R¹ and R² are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring; R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; p is 0 to 2; T is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6 atoms wherein the carbon atom of position 3 is connected to the carbon atom of position 4 to form a four to eight member ring; Z¹, Z², Z³, and Z⁴ are independently O, S, CR⁵R⁶, NR⁴, or N; and Z¹, Z², Z³, and Z⁴ are bonded to a sufficient number of hydrogen atoms or substituents to complete the valency of each atom with the proviso that Z¹, Z², Z³, and Z⁴ are not all heteroatoms and that not more than two adjacent atoms in Z¹, Z², Z³, and Z are heteroatoms and that in Formulae 2a, 2b, 2c, 2d, 2g and 2h, Z¹, Z², Z³, and Z⁴ are not all carbon atoms.
 11. The compound of claim 10, wherein the heteroatom of the hydrocarbon-heteroatom chain is is N, O, or S.
 12. The compound of claim 10, wherein T is substituted with 1 or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)₀₋₂CF₃, halogen, nitro, cyano, ═O, ═S, —OH, —SH, —CF₃, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆ alkyl, —CONR′R″, or —N(C₁-C₆alkyl)₂ where R′ and R″ are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.
 13. The compound of claim 10, wherein: T is —CH₂CH₂CO—O—, —CH₂—CH₂—O—CO—, —CH₂—CH₂—CH₂—CH₂—, —HC═CH—HC═CH—, —N═CH—HC═CH—, —HC═N—HC═CH—, —HC═CH—N═CH—, —HC═CH—HC═N—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—HC═CH—, —CH₂—CH₂—NH—CH₂—, —COCH═CH—O—, —O—CH═CH—CO—, —CH═CH—NR⁴—, —NR⁴—CH═CH—, —CH═CH—CH₂—, —CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—, —O—CH₂—CH₂—, —CH₂—CH₂—O—, —CH₂—CH₂₋CO—, —CH₂—CO—CH₂₋, —CO—CH₂—CH₂—, —CH₂—CH₂—CH₂—CO—, —CO—CH₂—CH₂—CH₂—, —CH₂—CO—CH₂—CH₂—, —CH₂—CH₂—CO—CH₂—, —CH₂—CH₂—CH₂—NR⁴—, —NR⁴—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—, —CO—NR⁴—CH₂—CH₂—, NR⁴CO—CH₂—CH₂—, —CH₂—CH₂₋NR⁴—CO—, or —CH₂—CH₂—CO—NR⁴—.
 14. A pharmaceutical composition comprising a compound of claim 1 and one or more carriers, diluents, or excipients.
 15. A method of treating, preventing or controlling non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 16. A method of treating, preventing or controlling obesity in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 17. A method of treating, preventing or controlling hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 18. A method of treating, preventing or controlling hyperlipidemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 19. A method of treating, preventing or controlling hypercholesteremia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 20. A method of treating preventing or controlling atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 21. A method of treating, preventing or controlling hypertriglyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 22. A method of treating, preventing or controlling hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of claim
 1. 23. A method of treating a patient exhibiting glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to the patient a therapeutically effective amount of a compound of claim
 1. 24. A method of making the compound having Formula 1:

or a pharmaceutically acceptable salt thereof, the method comprising reacting:

in a solvent in the presence of a base with:

wherein: R¹⁰ is a lower alkyl V¹ is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 1 is connected to the carbon atom of position 2 to form a five to eight member ring wherein the

 is attached to a substitutionally available position of said ring; X⁰ and X¹ are independently O or S; X² is absent, O, S, or NR⁴; X is a halogen; Ar¹ is substituted or unsubstituted aryl or heteroaryl; R¹, R², and R³ are independently hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy, —O(CH₂)_(p)CF₃, halogen, nitro, cyano, —OH, —SH, —CF₃, S(O)_(p)Alkyl, S(O)_(p)Aryl, —(CH₂)_(m)OR⁴, or —(CH₂)_(m)NR⁵R⁶, COR⁴, —CO₂H, —CO₂R⁴, —NR⁵R⁶; or —NR⁵R⁶or R1 and R2 are joined together to form a substituted or unsubstituted, saturated or unsaturated cyloalkyl or heterocycloalkyl ring; R⁴ is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, SO₂Alkyl or, SO₂Aryl, or joined together to form a 4 to 7 member ring having 1 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; and p is 0 to
 2. 25. A compound selected from: 5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-carboxylic acid; {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-2-yl}-acetic acid; 6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylic acid; {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic acid; {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-yl }-acetic acid; 5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylic acid; {6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}-acetic acid; {2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic acid; {2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic acid; {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic acid; {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl }-acetic acid; {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-acetic acid; 7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid; 7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-acetic acid; 7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-acetic acid; 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylic acid; 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylic acid; 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-acetic acid; {6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indan-1-yl}-acetic acid; 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-acetic acid; 3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionic acid; 6-Methoxy -5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-acetic acid; {6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid; {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid; {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-indol-1-yl}-acetic acid; and pharmaceutically acceptable salts thereof.
 26. A compound selected from: {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic acid, (2S); {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic acid, (2R); {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic acid, (2R); {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic acid, (2S); 6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylic acid, (2S); 6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylic acid, (2R); 2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylic acid, (2R); 2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-chroman-2-carboxylic acid, (2S); {7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-acetic acid, (2S); {7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-acetic acid, (2R); {4-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid; {2-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid; {3-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid; {6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol -5-ylmethoxy]-indol-1-yl}-acetic acid; 1-Carboxymethyl-2-methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol -5-ylmethoxy]-1H-indole-3-carboxylic acid ethyl ester; {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indol-3-yl}-acetic acid; {1-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indol-3-yl}-acetic acid; {5-Methoxy-1-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1H-indol-3-yl}-acetic acid; {5-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1H-indol-3-yl}-acetic acid; and pharmaceutically acceptable salts thereof. 